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Washida K, Saito S, Tanaka T, Nakaoku Y, Ishiyama H, Abe S, Kuroda T, Nakazawa S, Kakuta C, Omae K, Tanaka K, Minami M, Morita Y, Fukuda T, Shindo A, Maki T, Kitamura K, Tomimoto H, Aso T, Ihara M. A multicenter, single-arm, phase II clinical trial of adrenomedullin in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. CEREBRAL CIRCULATION - COGNITION AND BEHAVIOR 2024; 6:100211. [PMID: 38375188 PMCID: PMC10875187 DOI: 10.1016/j.cccb.2024.100211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/21/2024] [Accepted: 01/31/2024] [Indexed: 02/21/2024]
Abstract
Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary cerebral small vessel disease (SVD), currently lacks disease-modifying treatments. Adrenomedullin (AM), a vasoactive peptide with angiogenic, vasodilatory, anti-inflammatory, and anti-oxidative properties, shows potential effects on the neuro-glial-vascular unit. Objective The AdrenoMedullin for CADASIL (AMCAD) study aims to assess the efficacy and safety of AM in patients with CADASIL. Sample size Overall, 60 patients will be recruited. Methods The AMCAD is a multicenter, investigator-initiated, single-arm phase II trial. Patients with a confirmed CADASIL diagnosis, based on NOTCH3 genetic testing, will receive an 8-h AM treatment (15 ng/kg/min) for 14 days following a baseline assessment (from day 1 to day 14). Follow-up evaluations will be performed on days 15, 28, 90, and 180. Study outcomes The primary endpoint is the cerebral blood flow change rate in the frontal cortex, evaluated using arterial spin labeling magnetic resonance imaging, from baseline to day 28. Summary statistics, 95% confidence intervals, and a one-sample t-test will be used for analysis. Conclusion The AMCAD study aims to represent the therapeutic potential of AM in patients with CADASIL, addressing an unmet medical need in this challenging condition. Clinical Trial Registration jRCT 2,051,210,117 (https://jrct.niph.go.jp/en-latest-detail/jRCT2051210117).
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Affiliation(s)
- Kazuo Washida
- Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Satoshi Saito
- Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Tomotaka Tanaka
- Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Yuriko Nakaoku
- Department of Preventive Medicine and Epidemiology, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Hiroyuki Ishiyama
- Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Soichiro Abe
- Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Takehito Kuroda
- Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Shinsaku Nakazawa
- Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Chikage Kakuta
- Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Katsuhiro Omae
- Department of Data Science, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Kenta Tanaka
- Department of Data Science, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Manabu Minami
- Department of Data Science, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Yoshiaki Morita
- Department of Radiology, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Tetsuya Fukuda
- Department of Radiology, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Akihiro Shindo
- Department of Neurology, Mie University Graduate school of Medicine, Tsu, Japan
| | - Takakuni Maki
- Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kazuo Kitamura
- Department of Projects Research, Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan
| | - Hidekazu Tomimoto
- Department of Neurology, Mie University Graduate school of Medicine, Tsu, Japan
| | - Toshihiko Aso
- Laboratory for Brain Connectomics Imaging, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
| | - Masafumi Ihara
- Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan
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Bálint L, Nelson-Maney N, Tian Y, Serafin DS, Caron KM. Clinical Potential of Adrenomedullin Signaling in the Cardiovascular System. Circ Res 2023; 132:1185-1202. [PMID: 37104556 PMCID: PMC10155262 DOI: 10.1161/circresaha.123.321673] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 03/16/2023] [Indexed: 04/29/2023]
Abstract
Numerous clinical studies have revealed the utility of circulating AM (adrenomedullin) or MR-proAM (mid-regional proAM 45-92) as an effective prognostic and diagnostic biomarker for a variety of cardiovascular-related pathophysiologies. Thus, there is strong supporting evidence encouraging the exploration of the AM-CLR (calcitonin receptor-like receptor) signaling pathway as a therapeutic target. This is further bolstered because several drugs targeting the shared CGRP (calcitonin gene-related peptide)-CLR pathway are already Food and Drug Administration-approved and on the market for the treatment of migraine. In this review, we summarize the AM-CLR signaling pathway and its modulatory mechanisms and provide an overview of the current understanding of the physiological and pathological roles of AM-CLR signaling and the yet untapped potentials of AM as a biomarker or therapeutic target in cardiac and vascular diseases and provide an outlook on the recently emerged strategies that may provide further boost to the possible clinical applications of AM signaling.
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Affiliation(s)
- László Bálint
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill; 111 Mason Farm Road, Chapel Hill, North Carolina, USA 27599
| | - Nathan Nelson-Maney
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill; 111 Mason Farm Road, Chapel Hill, North Carolina, USA 27599
| | - Yanna Tian
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill; 111 Mason Farm Road, Chapel Hill, North Carolina, USA 27599
| | - D. Stephen Serafin
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill; 111 Mason Farm Road, Chapel Hill, North Carolina, USA 27599
| | - Kathleen M. Caron
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill; 111 Mason Farm Road, Chapel Hill, North Carolina, USA 27599
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Nakayama A, Roquid KA, Iring A, Strilic B, Günther S, Chen M, Weinstein LS, Offermanns S. Suppression of CCL2 angiocrine function by adrenomedullin promotes tumor growth. J Exp Med 2022; 220:213682. [PMID: 36374225 PMCID: PMC9665902 DOI: 10.1084/jem.20211628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/19/2022] [Accepted: 10/13/2022] [Indexed: 11/16/2022] Open
Abstract
Within the tumor microenvironment, tumor cells and endothelial cells regulate each other. While tumor cells induce angiogenic responses in endothelial cells, endothelial cells release angiocrine factors, which act on tumor cells and other stromal cells. We report that tumor cell-derived adrenomedullin has a pro-angiogenic as well as a direct tumor-promoting effect, and that endothelium-derived CC chemokine ligand 2 (CCL2) suppresses adrenomedullin-induced tumor cell proliferation. Loss of the endothelial adrenomedullin receptor CALCRL or of the G-protein Gs reduced endothelial proliferation. Surprisingly, tumor cell proliferation was also reduced after endothelial deletion of CALCRL or Gs. We identified CCL2 as a critical angiocrine factor whose formation is inhibited by adrenomedullin. Furthermore, CCL2 inhibited adrenomedullin formation in tumor cells through its receptor CCR2. Consistently, loss of endothelial CCL2 or tumor cell CCR2 normalized the reduced tumor growth seen in mice lacking endothelial CALCRL or Gs. Our findings show tumor-promoting roles of adrenomedullin and identify CCL2 as an angiocrine factor controlling adrenomedullin formation by tumor cells.
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Affiliation(s)
- Akiko Nakayama
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany,Correspondence to Akiko Nakayama:
| | - Kenneth Anthony Roquid
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - András Iring
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Boris Strilic
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Stefan Günther
- Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Min Chen
- Metabolic Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MA
| | - Lee S. Weinstein
- Metabolic Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MA
| | - Stefan Offermanns
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany,Center for Molecular Medicine, Goethe University Frankfurt, Frankfurt, Germany,Cardiopulmonary Institute, Bad Nauheim, Germany,German Center for Cardiovascular Research, Bad Nauheim, Germany,Stefan Offermanns:
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Jailani ABA, Bigos KJA, Avgoustou P, Egan JL, Hathway RA, Skerry TM, Richards GO. Targeting the adrenomedullin-2 receptor for the discovery and development of novel anti-cancer agents. Expert Opin Drug Discov 2022; 17:839-848. [PMID: 35733389 DOI: 10.1080/17460441.2022.2090541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Adrenomedullin (AM) is a peptide responsible for many physiological processes including vascular health and hormone regulation. Dysregulation of AM signaling can stimulate cancers by promoting proliferation, angiogenesis and metastasis. Two AM receptors contribute to tumor progression in different ways. Adrenomedullin-1 receptor (AM1R) regulates blood pressure and blocking AM signaling via AM1R would be clinically unacceptable. Therefore, antagonizing adrenomedullin-2 receptor (AM2R) presents as an avenue for anti-cancer drug development. AREAS COVERED We review the literature to highlight AM's role in cancer as well as delineating the specific roles AM1R and AM2R mediate in the development of a pro-tumoral microenvironment. We highlight the importance of exploring the residue differences between the receptors that led to the development of first-in-class selective AM2R small molecule antagonists. We also summarize the current approaches targeting AM and its receptors, their anti-tumor effects and their limitations. EXPERT OPINION As tool compounds, AM2R antagonists will allow the dissection of the functions of CGRPR (calcitonin gene-related peptide receptor), AM1R and AM2R, and has considerable potential as a first-in-class oncology therapy. Furthermore, the lack of detectable side effects and good drug-like pharmacokinetic properties of these AM2R antagonists support the promise of this class of compounds as potential anti-cancer therapeutics.
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Affiliation(s)
- Ameera B A Jailani
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Kamilla J A Bigos
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Paris Avgoustou
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Joseph L Egan
- Department of Chemistry, University of Sheffield, Sheffield, UK
| | | | - Timothy M Skerry
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Gareth O Richards
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
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Kita T, Kitamura K. Translational studies of adrenomedullin and related peptides regarding cardiovascular diseases. Hypertens Res 2022; 45:389-400. [PMID: 34992239 PMCID: PMC8732970 DOI: 10.1038/s41440-021-00806-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/24/2021] [Accepted: 10/28/2021] [Indexed: 12/11/2022]
Abstract
Adrenomedullin (AM) is a vasodilative peptide with various physiological functions, including the maintenance of vascular tone and endothelial barrier function. AM levels are markedly increased during severe inflammation, such as that associated with sepsis; thus, AM is expected to be a useful clinical marker and therapeutic agent for inflammation. However, as the increase in AM levels in cardiovascular diseases (CVDs) is relatively low compared to that in infectious diseases, the value of AM as a marker of CVDs seems to be less important. Limitations pertaining to the administrative route and short half-life of AM in the bloodstream (<30 min) restrict the therapeutic applications of AM for CVDs. In early human studies, various applications of AM for CVDs were attempted, including for heart failure, myocardial infarction, pulmonary hypertension, and peripheral artery disease; however, none achieved success. We have developed AM as a therapeutic agent for inflammatory bowel disease in which the vasodilatory effect of AM is minimized. A clinical trial evaluating this AM formulation for acute cerebral infarction is ongoing. We have also developed AM derivatives that exhibit a longer half-life and less vasodilative activity. These AM derivatives can be administered by subcutaneous injection at long-term intervals. Accordingly, these derivatives will reduce the inconvenience in use compared to that for native AM and expand the possible applications of AM for treating CVDs. In this review, we present the latest translational status of AM and its derivatives.
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Affiliation(s)
- Toshihiro Kita
- Department of Projects Research, Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan.
| | - Kazuo Kitamura
- Department of Projects Research, Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan
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Chang CL, Lo WC, Lee TH, Sung JY, Sung YJ. Oocyte-specific disruption of adrenomedullin 2 gene enhances ovarian follicle growth after superovulation. Front Endocrinol (Lausanne) 2022; 13:1047498. [PMID: 36452323 PMCID: PMC9702065 DOI: 10.3389/fendo.2022.1047498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Accepted: 10/24/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Adrenomedullin 2 (ADM2), adrenomedullin (ADM), and calcitonin gene-related peptides (α- and β-CGRPs) signal through heterodimeric calcitonin receptor-like receptor/receptor activity-modifying protein 1, 2 and 3 (CLR/RAMP1, 2 and 3) complexes. These peptides are important regulators of neurotransmission, vasotone, cardiovascular development, and metabolic homeostasis. In rodents, ADM is essential for regulating embryo implantation, fetal-placental development, and hemodynamic adaptation during pregnancy. On the other hand, ADM2 was shown to affect vascular lumen enlargement, and cumulus cell-oocyte complex (COC) communication in rodent and bovine ovarian follicles. To investigate whether oocyte-derived ADM2 plays a physiological role in regulating ovarian folliculogenesis, we generated mice with oocyte-specific disruption of the Adm2 gene using a LoxP-flanked Adm2 transgene (Adm2 loxP/loxP) and crossed them with Zp3-Cre mice which carry a zona pellucida 3 (Zp3) promoter-Cre recombinase transgene. RESULTS While heterozygous Adm2 +/-/Zp3-Cre and homozygous Adm2 -/-/Zp3-Cre mice were fertile, Adm2 disruption in oocytes significantly increased the number of ovulated oocytes following a superovulation treatment. Oocyte-specific Adm2 disruption also significantly impaired the developmental capacity of fertilized eggs and decreased the size of the corpus luteum following superovulation, perhaps due to a reduction of ovarian cyclin D2-associated signaling. CONCLUSIONS The disruption of intrafollicular ADM2 signaling leads to follicular dysfunction. These data suggested that oocyte-derived ADM2 plays a facilitative role in the regulation of hormonal response and follicle growth independent of the closely related ADM and CGRP peptides, albeit in a subtle manner.
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Li Y, Lyu P, Ze Y, Li P, Zeng X, Shi Y, Qiu B, Gong P, Yao Y. Exosomes derived from plasma: promising immunomodulatory agents for promoting angiogenesis to treat radiation-induced vascular dysfunction. PeerJ 2021; 9:e11147. [PMID: 33859878 PMCID: PMC8020864 DOI: 10.7717/peerj.11147] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 03/03/2021] [Indexed: 02/05/2023] Open
Abstract
Ionizing radiation (IR)-induced vascular disorders slow down tissue regeneration. Exosomes derived from plasma exhibit potential to promote angiogenesis; meanwhile, the immune microenvironment plays a significant role in the process. This study aimed to test the hypothesis that plasma exosomes promote angiogenesis in irradiated tissue by mediating the immune microenvironment. First, we explored the impact of IR on macrophages. We found that cell viability and capacity for promoting angiogenesis were decreased in irradiated macrophages compared to control macrophages. Then, we isolated and characterized rat plasma-derived exosomes (RP-Exos) which were defined as 40-160 nm extracellular vesicles extracted from rat plasma. Afterward, we evaluated the effects of RP-Exos on the behaviors of irradiated macrophages. Our results show that RP-Exos promoted cell proliferation. More importantly, we found that RP-Exos stimulated the immune microenvironment in a manner that improved the angiogenesis-related genes and proteins of irradiated macrophages. The supernatant of macrophage cell cultures was used as conditioned medium to treat human primary umbilical vein endothelial cells, further confirming the pro-angiogenic ability of macrophages receiving RP-Exo intervention. RP-Exos were used in vivo to treat irradiated skin or calvarial defects in irradiated Sprague-Dawley male rats. The results indicated the ability of RP-Exos to enhance angiogenesis and promote tissue regeneration. Our research suggested the potential of plasma exosomes to be used as immunomodulatory agents with angiogenic capacity to treat radiation-associated vascular disorders and facilitate tissue repair.
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Affiliation(s)
- Yanxi Li
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Ping Lyu
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yiting Ze
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Peiran Li
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Xinyi Zeng
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yixin Shi
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Bingrun Qiu
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Ping Gong
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yang Yao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
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Tanaka M, Kakihara S, Hirabayashi K, Imai A, Toriyama Y, Iesato Y, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Cui N, Wei Y, Zhao Y, Aruga K, Yamauchi A, Murata T, Shindo T. Adrenomedullin-Receptor Activity-Modifying Protein 2 System Ameliorates Subretinal Fibrosis by Suppressing Epithelial-Mesenchymal Transition in Age-Related Macular Degeneration. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:652-668. [PMID: 33385343 DOI: 10.1016/j.ajpath.2020.12.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 12/08/2020] [Accepted: 12/17/2020] [Indexed: 01/06/2023]
Abstract
Age-related macular degeneration (AMD) is a leading cause of visual impairment. Anti-vascular endothelial growth factor drugs used to treat AMD carry the risk of inducing subretinal fibrosis. We investigated the use of adrenomedullin (AM), a vasoactive peptide, and its receptor activity-modifying protein 2, RAMP2, which regulate vascular homeostasis and suppress fibrosis. The therapeutic potential of the AM-RAMP2 system was evaluated after laser-induced choroidal neovascularization (LI-CNV), a mouse model of AMD. Neovascular formation, subretinal fibrosis, and macrophage invasion were all enhanced in both AM and RAMP2 knockout mice compared with those in wild-type mice. These pathologic changes were suppressed by intravitreal injection of AM. Comprehensive gene expression analysis of the choroid after LI-CNV with or without AM administration revealed that fibrosis-related molecules, including Tgfb, Cxcr4, Ccn2, and Thbs1, were all down-regulated by AM. In retinal pigment epithelial cells, co-administration of transforming growth factor-β and tumor necrosis factor-α induced epithelial-mesenchymal transition, which was also prevented by AM. Finally, transforming growth factor-β and C-X-C chemokine receptor type 4 (CXCR4) inhibitors eliminated the difference in subretinal fibrosis between RAMP2 knockout and wild-type mice. These findings suggest the AM-RAMP2 system suppresses subretinal fibrosis in LI-CNV by suppressing epithelial-mesenchymal transition.
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Affiliation(s)
- Masaaki Tanaka
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Japan
| | - Shinji Kakihara
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Japan
| | | | - Akira Imai
- Department of Ophthalmology, Shinshu University School of Medicine, Japan
| | - Yuichi Toriyama
- Department of Ophthalmology, Shinshu University School of Medicine, Japan
| | - Yasuhiro Iesato
- Department of Ophthalmology, Shinshu University School of Medicine, Japan
| | - Takayuki Sakurai
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan; Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano, Japan
| | - Akiko Kamiyoshi
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan; Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano, Japan
| | - Yuka Ichikawa-Shindo
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hisaka Kawate
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
| | - Megumu Tanaka
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
| | - Nanqi Cui
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yangxuan Wei
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yunlu Zhao
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
| | - Kohsuke Aruga
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akihiro Yamauchi
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
| | - Toshinori Murata
- Department of Ophthalmology, Shinshu University School of Medicine, Japan
| | - Takayuki Shindo
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan; Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano, Japan.
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Cui N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Tanaka M, Wei Y, Kakihara S, Zhao Y, Aruga K, Kawagishi H, Nakada T, Yamada M, Shindo T. Adrenomedullin-RAMP2 and -RAMP3 Systems Regulate Cardiac Homeostasis during Cardiovascular Stress. Endocrinology 2021; 162:6129198. [PMID: 33545715 DOI: 10.1210/endocr/bqab001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Indexed: 12/26/2022]
Abstract
Adrenomedullin (AM) is a peptide hormone with multiple physiological functions, which are regulated by its receptor activity-modifying proteins, RAMP2 and RAMP3. We previously reported that AM or RAMP2 knockout (KO) (AM-/-, RAMP2-/-) is embryonically lethal in mice, whereas RAMP3-/- mice are apparently normal. AM, RAMP2, and RAMP3 are all highly expressed in the heart; however, their functions there are not fully understood. Here, we analyzed the pathophysiological functions of the AM-RAMP2 and AM-RAMP3 systems in hearts subjected to cardiovascular stress. Cardiomyocyte-specific RAMP2-/- (C-RAMP2-/-) and RAMP3-/- showed no apparent heart failure at base line. After 1 week of transverse aortic constriction (TAC), however, C-RAMP2-/- exhibited significant cardiac hypertrophy, decreased ejection fraction, and increased fibrosis compared with wild-type mice. Both dP/dtmax and dP/dtmin were significantly reduced in C-RAMP2-/-, indicating reduced ventricular contractility and relaxation. Exposing C-RAMP2-/- cardiomyocytes to isoproterenol enhanced their hypertrophy and oxidative stress compared with wild-type cells. C-RAMP2-/- cardiomyocytes also contained fewer viable mitochondria and showed reduced mitochondrial membrane potential and respiratory capacity. RAMP3-/- also showed reduced systolic function and enhanced fibrosis after TAC, but those only became apparent after 4 weeks. A reduction in cardiac lymphatic vessels was the characteristic feature in RAMP3-/-. These observations indicate the AM-RAMP2 system is necessary for early adaptation to cardiovascular stress through regulation of cardiac mitochondria. AM-RAMP3 is necessary for later adaptation through regulation of lymphatic vessels. The AM-RAMP2 and AM-RAMP3 systems thus play separate critical roles in the maintenance of cardiovascular homeostasis against cardiovascular stress.
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Affiliation(s)
- Nanqi Cui
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takayuki Sakurai
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
- Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan
| | - Akiko Kamiyoshi
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
- Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan
| | - Yuka Ichikawa-Shindo
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hisaka Kawate
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
| | - Megumu Tanaka
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
| | - Masaaki Tanaka
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yangxuan Wei
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shinji Kakihara
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yunlu Zhao
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
| | - Kohsuke Aruga
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hiroyuki Kawagishi
- Department of Molecular Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan
- Department of Biotechnology, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan
| | - Tsutomu Nakada
- Department of Instrumental Analysis, Research Center for Supports to Advanced Science, Shinshu University, Matsumoto, Japan
| | - Mitsuhiko Yamada
- Department of Molecular Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takayuki Shindo
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan
- Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan
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Vázquez R, Riveiro ME, Berenguer-Daizé C, O'Kane A, Gormley J, Touzelet O, Rezai K, Bekradda M, Ouafik L. Targeting Adrenomedullin in Oncology: A Feasible Strategy With Potential as Much More Than an Alternative Anti-Angiogenic Therapy. Front Oncol 2021; 10:589218. [PMID: 33489885 PMCID: PMC7815935 DOI: 10.3389/fonc.2020.589218] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 11/02/2020] [Indexed: 12/18/2022] Open
Abstract
The development, maintenance and metastasis of solid tumors are highly dependent on the formation of blood and lymphatic vessels from pre-existing ones through a series of processes that are respectively known as angiogenesis and lymphangiogenesis. Both are mediated by specific growth-stimulating molecules, such as the vascular endothelial growth factor (VEGF) and adrenomedullin (AM), secreted by diverse cell types which involve not only the cancerogenic ones, but also those constituting the tumor stroma (i.e., macrophages, pericytes, fibroblasts, and endothelial cells). In this sense, anti-angiogenic therapy represents a clinically-validated strategy in oncology. Current therapeutic approaches are mainly based on VEGF-targeting agents, which, unfortunately, are usually limited by toxicity and/or tumor-acquired resistance. AM is a ubiquitous peptide hormone mainly secreted in the endothelium with an important involvement in blood vessel development and cardiovascular homeostasis. In this review, we will introduce the state-of-the-art in terms of AM physiology, while putting a special focus on its pro-tumorigenic role, and discuss its potential as a therapeutic target in oncology. A large amount of research has evidenced AM overexpression in a vast majority of solid tumors and a correlation between AM levels and disease stage, progression and/or vascular density has been observed. The analysis presented here indicates that the involvement of AM in the pathogenesis of cancer arises from: 1) direct promotion of cell proliferation and survival; 2) increased vascularization and the subsequent supply of nutrients and oxygen to the tumor; 3) and/or alteration of the cell phenotype into a more aggressive one. Furthermore, we have performed a deep scrutiny of the pathophysiological prominence of each of the AM receptors (AM1 and AM2) in different cancers, highlighting their differential locations and functions, as well as regulatory mechanisms. From the therapeutic point of view, we summarize here an exhaustive series of preclinical studies showing a reduction of tumor angiogenesis, metastasis and growth following treatment with AM-neutralizing antibodies, AM receptor antagonists, or AM receptor interference. Anti-AM therapy is a promising strategy to be explored in oncology, not only as an anti-angiogenic alternative in the context of acquired resistance to VEGF treatment, but also as a potential anti-metastatic approach.
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Affiliation(s)
- Ramiro Vázquez
- Preclinical Department, Early Drug Development Group (E2DG), Boulogne-Billancourt, France.,Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy
| | - Maria E Riveiro
- Preclinical Department, Early Drug Development Group (E2DG), Boulogne-Billancourt, France
| | | | - Anthony O'Kane
- Discovery and Scientific Affairs Department, Fusion Antibodies plc., Belfast, United Kingdom
| | - Julie Gormley
- Discovery and Scientific Affairs Department, Fusion Antibodies plc., Belfast, United Kingdom
| | - Olivier Touzelet
- Discovery and Scientific Affairs Department, Fusion Antibodies plc., Belfast, United Kingdom
| | - Keyvan Rezai
- Department of Radio-Pharmacology, Institute Curie-René Huguenin Hospital, Saint-Cloud, France
| | - Mohamed Bekradda
- Preclinical Department, Early Drug Development Group (E2DG), Boulogne-Billancourt, France
| | - L'Houcine Ouafik
- Aix Marseille University, CNRS, INP, Institute of NeuroPhysiopathology, Marseille, France.,APHM, CHU Nord, Service de Transfert d'Oncologie Biologique, Marseille, France
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11
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Hu C, Chen B, Huang Z, Liu C, Ye L, Wang C, Tong Y, Yang J, Zhao C. Comprehensive profiling of immune-related genes in soft tissue sarcoma patients. J Transl Med 2020; 18:337. [PMID: 32873319 PMCID: PMC7465445 DOI: 10.1186/s12967-020-02512-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 08/27/2020] [Indexed: 02/08/2023] Open
Abstract
Background Immune-related genes (IRGs) have been confirmed to have an important role in tumorigenesis and tumor microenvironment formation. Nevertheless, a systematic analysis of IRGs and their clinical significance in soft tissue sarcoma (STS) patients is lacking. Methods Gene expression files from The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression (GTEx) were used to select differentially expressed genes (DEGs). Differentially expressed immune-related genes (DEIRGs) were determined by matching the DEG and ImmPort gene sets, which were evaluated by functional enrichment analysis. Unsupervised clustering of the identified DEIRGs was conducted, and associations with prognosis, the tumor microenvironment (TME), immune checkpoints, and immune cells were analyzed simultaneously. Two prognostic signatures, one for overall survival (OS) and one for progression free survival (PFS), were established and validated in an independent set. Finally, two transcription factor (TF)-IRG regulatory networks were constructed, and a crucial regulatory axis was validated. Results In total, 364 DEIRGs and four clusters were identified. OS, TME scores, five immune checkpoints, and 12 types of immune cells were found to be significantly different among the four clusters. The two prognostic signatures incorporating 20 DEIRGs showed favorable discrimination and were successfully validated. Two nomograms combining signature and clinical variables were generated. The C-indexes were 0.879 (95%CI 0.832 ~ 0.926) and 0.825 (95%CI 0.776 ~ 0.874) for the OS and PFS signatures, respectively. Finally, TF-IRG regulatory networks were established, and the MYH11-ADM regulatory axis was verified in three independent datasets. Conclusion This comprehensive analysis of the IRG landscape in soft tissue sarcoma revealed novel IRGs related to carcinogenesis and the immune microenvironment. These findings have implications for prognosis and therapeutic responses, which reveal novel potential prognostic biomarkers, promote precision medicine, and provide potential novel targets for immunotherapy.
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Affiliation(s)
- Chuan Hu
- Department of Orthopedic, Affiliated Hospital of Chengde Medical University, Hebei, China.,Qingdao University Medical College, Shandong, 266071, China
| | - Bo Chen
- Department of Orthopedic, Affiliated Hospital of Chengde Medical University, Hebei, China.,Wenzhou Medical University, Zhejiang, 325000, China
| | - Zhangheng Huang
- Department of Orthopedic, Affiliated Hospital of Chengde Medical University, Hebei, China
| | - Chuan Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Lin Ye
- Wenzhou Medical University, Zhejiang, 325000, China
| | - Cailin Wang
- Wenzhou Medical University, Zhejiang, 325000, China
| | - Yuexin Tong
- Department of Orthopedic, Affiliated Hospital of Chengde Medical University, Hebei, China
| | - Jiaxin Yang
- Wenzhou Medical University, Zhejiang, 325000, China
| | - Chengliang Zhao
- Department of Orthopedic, Affiliated Hospital of Chengde Medical University, Hebei, China.
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12
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Endogenous Calcitonin Gene–Related Peptide Deficiency Exacerbates Postoperative Lymphedema by Suppressing Lymphatic Capillary Formation and M2 Macrophage Accumulation. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:2487-2502. [DOI: 10.1016/j.ajpath.2019.08.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 08/08/2019] [Accepted: 08/15/2019] [Indexed: 02/06/2023]
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13
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Deficiency of the adrenomedullin-RAMP3 system suppresses metastasis through the modification of cancer-associated fibroblasts. Oncogene 2019; 39:1914-1930. [PMID: 31754214 DOI: 10.1038/s41388-019-1112-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 11/06/2019] [Accepted: 11/08/2019] [Indexed: 02/07/2023]
Abstract
Tumor metastasis is a primary source of morbidity and mortality in cancer. Adrenomedullin (AM) is a multifunctional peptide regulated by receptor activity-modifying proteins (RAMPs). We previously reported that the AM-RAMP2 system is involved in tumor angiogenesis, but the function of the AM-RAMP3 system remains largely unknown. Here, we investigated the actions of the AM-RAMP2 and 3 systems in the tumor microenvironment and their impact on metastasis. PAN02 pancreatic cancer cells were injected into the spleens of mice, leading to spontaneous liver metastasis. Tumor metastasis was enhanced in vascular endothelial cell-specific RAMP2 knockout mice (DI-E-RAMP2-/-). By contrast, metastasis was suppressed in RAMP3-/- mice, where the number of podoplanin (PDPN)-positive cancer-associated fibroblasts (CAFs) was reduced in the periphery of tumors at metastatic sites. Because PDPN-positive CAFs are a hallmark of tumor malignancy, we assessed the regulation of PDPN and found that Src/Cas/PDPN signaling is mediated by RAMP3. In fact, RAMP3 deficiency CAFs suppressed migration, proliferation, and metastasis in co-cultures with tumor cells in vitro and in vivo. Moreover, the activation of RAMP2 in RAMP3-/- mice suppressed both tumor growth and metastasis. Based on these results, we suggest that the upregulation of PDPN in DI-E-RAMP2-/- mice increases malignancy, while the downregulation of PDPN in RAMP3-/- mice reduces it. Selective activation of RAMP2 and inhibition of RAMP3 would therefore be expected to suppress tumor metastasis. This study provides the first evidence that understanding and targeting to AM-RAMP systems could contribute to the development of novel therapeutics against metastasis.
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14
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Lee DH, Kim TM, Kim JK, Park C. ETV2/ER71 Transcription Factor as a Therapeutic Vehicle for Cardiovascular Disease. Theranostics 2019; 9:5694-5705. [PMID: 31534512 PMCID: PMC6735401 DOI: 10.7150/thno.35300] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 06/26/2019] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular diseases have long been the leading cause of mortality and morbidity in the United States as well as worldwide. Despite numerous efforts over the past few decades, the number of the patients with cardiovascular disease still remains high, thereby necessitating the development of novel therapeutic strategies equipped with a better understanding of the biology of the cardiovascular system. Recently, the ETS transcription factor, ETV2 (also known as ER71), has been recognized as a master regulator of the development of the cardiovascular system and plays an important role in pathophysiological angiogenesis and the endothelial cell reprogramming. Here, we discuss the detailed mechanisms underlying ETV2/ER71-regulated cardiovascular lineage development. In addition, recent reports on the novel functions of ETV2/ER71 in neovascularization and direct cell reprogramming are discussed with a focus on its therapeutic potential for cardiovascular diseases.
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15
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Chang CL, Hsu SYT. Development of chimeric and bifunctional antagonists for CLR/RAMP receptors. PLoS One 2019; 14:e0216996. [PMID: 31150417 PMCID: PMC6544337 DOI: 10.1371/journal.pone.0216996] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 05/02/2019] [Indexed: 11/26/2022] Open
Abstract
CGRP, adrenomedullin (ADM), and adrenomedullin 2 (ADM2) family peptides are
important neuropeptides and hormones for the regulation of neurotransmission,
vasotone, cardiovascular morphogenesis, vascular integrity, and feto‒placental
development. These peptides signal through CLR/RAMP1, 2 and 3 receptor
complexes. CLR/RAMP1, or CGRP receptor, antagonists have been developed for the
treatment of migraine headache and osteoarthritis pain; whereas CLR/RAMP2, or
ADM receptor, antagonists are being developed for the treatment of tumor
growth/metastasis. Based on the finding that an acylated chimeric ADM/ADM2
analog potently stimulates CLR/RAMP1 and 2 signaling, we hypothesized that the
binding domain of this analog could have potent inhibitory activity on CLR/RAMP
receptors. Consistent with this hypothesis, we showed that acylated truncated
ADM/ADM2 analogs of 27–31 residues exhibit potent antagonistic activity toward
CLR/RAMP1 and 2. On the other hand, nonacylated analogs have minimal activity.
Further truncation at the junctional region of these chimeric analogs led to the
generation of CLR/RAMP1-selective antagonists. A 17-amino-acid analog
(Antagonist 2–4) showed 100-fold selectivity for CLR/RAMP1 and was >100-fold
more potent than the classic CGRP receptor antagonist CGRP8-37. In addition, we
showed (1) a lysine residue in the Antagonist 2–4 is important for enhancing the
antagonistic activity, (2) an analog consisted of an ADM sequence motif and a
12-amino-acid binding domain of CGRP exhibits potent CLR/RAMP1-inhibitory
activity, and (3) a chimeric analog consisted of a somatostatin analog and an
ADM antagonist exhibits dual activities on somatostatin and CLR/RAMP receptors.
Because the blockage of CLR/RAMP signaling prevents migraine pain and suppresses
tumor growth/metastasis, further studies of these analogs, which presumably have
better access to the tumor microenvironment and nerve endings at the trigeminal
ganglion and synovial joints as compared to antibody-based therapies, may lead
to the development of better anti-CGRP therapy and alternative antiangiogenesis
therapy. Likewise, the use of bifunctional somatostatin-ADM antagonist analogs
could be a promising strategy for the treatment of high-grade neuroendocrine
tumors by targeting an antiangiogenesis agent to the neuroendocrine tumor
microenvironment.
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Affiliation(s)
- Chia Lin Chang
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital
Linkou Medical Center, Chang Gung University, Kweishan, Taoyuan,
Taiwan
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16
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Ozcelik F, Pence HH, Ozturkeri HY, Sertoğlu E. Adrenomedullin as a Protein with Multifunctional Behavior and Effects in Various Organs and Tissues. ACTA ACUST UNITED AC 2019. [DOI: 10.14302/issn.2641-9181.ijnr-19-2771] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
In literature, it has been reported that adrenomedullin, which is generally thought to have vasodilator, natriuretic and diuretic effects, is synthesized in almost all body, especially CNS, vascular muscles and endothelium, heart, liver, lung, kidney, gastric mocosa, intestinal endothelium and various blood cells. It has been found that the possible effects of adrenomedullin can be demonstrated directly or indirectly by means of active mediators, neuropeptides, enzymes and hormones. It is also suggested that it regulates the endocrine system by affecting the hypothalamic-pituitary axis. It increases in heart failure, acute coronary syndromes, hypertensive conditions, cerebrovascular accessory, chronic renal failure and periodontitis and decreases in peptic ulcer and intestinal diseases. However, it is still not clear whether increase/decrease in adrenomedullin level is a cause of a disease or is a result of damage due to an illness. This peptide, which could be thought to multifunctional, should be considered as a molecule with genetic coding that may have different effects on different tissues and conditions. For all these reasons, we aimed to review the multifonctional behavior of adrenomedullin in the light of the current literature to pioneer new hypotheses and discuss possible mechanisms.
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Affiliation(s)
- Fatih Ozcelik
- University of Health Sciences, Faculty of Medicine, Department of Medical Biochemistry, Istanbul, Turkey
| | - Halime Hanim Pence
- University of Health Sciences, Faculty of Medicine, Department of Medical Biochemistry, Istanbul, Turkey
| | - Hilal Yalcin Ozturkeri
- University of Health Sciences, Haydarpasa Numune Training Hospital, Department of Medical Biochemistry, Istanbul, Turkey
| | - Erdim Sertoğlu
- University of Health Sciences, Gulhane Faculty of Medicine, Department of Medical Biochemistry, Istanbul, Turkey
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17
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Hirabayashi K, Tanaka M, Imai A, Toriyama Y, Iesato Y, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Dai K, Cui N, Wei Y, Nakamura K, Iida S, Matsui S, Yamauchi A, Murata T, Shindo T. Development of a Novel Model of Central Retinal Vascular Occlusion and the Therapeutic Potential of the Adrenomedullin-Receptor Activity-Modifying Protein 2 System. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:449-466. [PMID: 30658846 DOI: 10.1016/j.ajpath.2018.10.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 10/03/2018] [Accepted: 10/23/2018] [Indexed: 12/20/2022]
Abstract
Central retinal vein occlusion (CRVO) is an intractable disease that causes visual acuity loss with retinal ischemia, hemorrhage, and edema. In this study, we developed an experimental CRVO model in mice and evaluated the therapeutic potential of the pleiotropic peptide adrenomedullin (ADM) and its receptor activity-modifying protein 2 (RAMP2). The CRVO model, which had phenotypes resembling those seen in the clinic, was produced by combining i.p. injection of Rose bengal, a photoactivator dye enhancing thrombus formation, with laser photocoagulation. Retinal vascular area, analyzed using fluorescein angiography and fluorescein isothiocyanate-perfused retinal flat mounts, was decreased after induction of CRVO but gradually recovered from day 1 to 7. Measurements of retinal thickness using optical coherence tomography and histology revealed prominent edema early after CRVO, followed by gradual atrophy. Reperfusion after CRVO was diminished in Adm and Ramp2 knockout (KO) mice but was increased by exogenous ADM administration. CRVO also increased expression of a coagulation factor, oxidative stress markers, and a leukocyte adhesion molecule in both wild-type and Adm KO mice, and the effect was more pronounced in Adm KO mice. Using retinal capillary endothelial cells, ADM was found to directly suppress retinal endothelial injury. The retinoprotective effects of the Adm-Ramp2 system make it a novel therapeutic target for the treatment of CRVO.
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Affiliation(s)
- Kazutaka Hirabayashi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Masaaki Tanaka
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Akira Imai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Yuichi Toriyama
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Yasuhiro Iesato
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Takayuki Sakurai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Akiko Kamiyoshi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Yuka Ichikawa-Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Hisaka Kawate
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Megumu Tanaka
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Kun Dai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Nanqi Cui
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Yangxuan Wei
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Keisei Nakamura
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Shiho Iida
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Shuhei Matsui
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Anesthesiology, Shinshu University School of Medicine, Nagano, Japan
| | | | - Toshinori Murata
- Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Takayuki Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
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18
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Shindo T, Tanaka M, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Yamauchi A, Sakurai T. Regulation of cardiovascular development and homeostasis by the adrenomedullin-RAMP system. Peptides 2019; 111:55-61. [PMID: 29689347 DOI: 10.1016/j.peptides.2018.04.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 04/05/2018] [Accepted: 04/09/2018] [Indexed: 11/18/2022]
Abstract
Adrenomedullin (AM), a member of the calcitonin peptide superfamily, is a peptide involved in both the pathogenesis of cardiovascular diseases and circulatory homeostasis. Its receptor, calcitonin receptor-like receptor (CLR), associates with an accessory protein, receptor activity-modifying protein (RAMP). Depending upon which the three RAMP isoforms (RAMP1-3) it interacts with, CLR functions as a receptor for AM or other calcitonin family peptides. AM knockout mice (-/-) died mid-gestation due to abnormalities in vascular development. We found that phenotypes similar to AM-/- were reproduced only in RAMP2-/- mice. We generated endothelial cell-specific RAMP2 knockout mice (E-RAMP2-/-) and found most E-RAMP2-/- mice died perinatally. In surviving adults, vasculitis and organ fibrosis occurred spontaneously. We next generated drug-inducible cardiac myocyte-specific RAMP2-/- (DI-C-RAMP2-/-) mice, which exhibited dilated cardiomyopathy-like heart failure with cardiac dilatation and myofibril disruption. DI-C-RAMP2-/- hearts also showed changes in mitochondrial structure and downregulation of mitochondria-related genes involved in oxidative phosphorylation and β-oxidation. In contrast to RAMP2-/- mice, RAMP3-/- mice were born with no major abnormalities. In adult RAMP3-/- mice, postnatal angiogenesis was normal, but drainage of subcutaneous lymphatic vessels was delayed. RAMP3-/- mice also showed more severe interstitial edema than in wild-type mice in a tail lymphedema model. These findings show that the AM-RAMP system is a key determinant of cardiovascular integrity and homeostasis from prenatal stages through adulthood. The AM-RAMP2 system mainly regulates vascular development and homeostasis, while the AM-RAMP3 system mainly regulates lymphatic function in adults. The AM-RAMP system may thus have therapeutic potential for the treatment of cardiovascular diseases.
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Affiliation(s)
- Takayuki Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
| | - Megumu Tanaka
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Akiko Kamiyoshi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Yuka Ichikawa-Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Hisaka Kawate
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Akihiro Yamauchi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Japan Bio Products Co., Ltd., Tokyo, Japan
| | - Takayuki Sakurai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
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Daukantaitė D, Tellhed U, Maddux RE, Svensson T, Melander O. Five-week yin yoga-based interventions decreased plasma adrenomedullin and increased psychological health in stressed adults: A randomized controlled trial. PLoS One 2018; 13:e0200518. [PMID: 30020987 PMCID: PMC6051627 DOI: 10.1371/journal.pone.0200518] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 06/25/2018] [Indexed: 12/20/2022] Open
Abstract
Background Non-communicable diseases (NCDs, e.g. cardiovascular disease) are responsible for high rates of morbidity and the majority of premature deaths worldwide. It is necessary to develop preventative interventions that can reduce the associated risk factors of NCDs. Researchers have found that the biomarker adrenomedullin (ADM) becomes elevated years before the onset of NCDs and might play an important role in their development. ADM has also been linked to psychological problems such as stress, anxiety, and depression, which are known risk factors of NCDs. In this randomized controlled trial, we examined whether participating in a five-week yoga intervention reduces ADM and increases psychological health in middle-aged adults who self-report as moderately to highly stressed, but who otherwise exhibit no physical complaints. Methods One hundred and five adults (78% women; mean age = 53.5, SD = 6.7) were randomly assigned to (1) a five-week Yin yoga intervention, (2) a five-week intervention combining Yin yoga with psychoeducation and mindfulness practice (called the YOMI program), or (3) a control group who did not practice yoga or mindfulness for five weeks. Results Compared to the control group, we observed significantly greater pre-post reductions in plasma ADM levels (p < .001), anxiety (p ≤ .002), and sleep problems (p ≤ .003) in both intervention groups. Furthermore, the YOMI group exclusively showed significantly greater pre-post reductions in stress (p = .012) and depression (p = .021) compared to the control group. Significant correlations (p < .05) were found between pre-post reductions in ADM and anxiety symptoms (p = .02) and depression (p = .04) in the entire sample. Conclusion The five-week Yin yoga-based interventions appeared to reduce both the physiological and psychological risk factors known to be associated with NCDs. The study suggests that incorporating Yin yoga could be an easy and low-cost method of limiting the negative health effects associated with high stress. Trial registration ClinicalTrials.gov NCT03428542
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Affiliation(s)
| | - Una Tellhed
- Department of Psychology, Lund University, Lund, Sweden
| | | | - Thomas Svensson
- Department of Clinical Sciences, Lund University, Lund, Sweden
- Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Olle Melander
- Department of Clinical Sciences, Lund University, Lund, Sweden
- Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden
- * E-mail:
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Molina F, Del Moral ML, Peinado MÁ, Rus A. Angiogenesis is VEGF-independent in the aged striatum of male rats exposed to acute hypoxia. Biogerontology 2017; 18:759-768. [PMID: 28501895 DOI: 10.1007/s10522-017-9709-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Accepted: 05/09/2017] [Indexed: 10/19/2022]
Abstract
Brain hypoxia is involved in many diseases. The activation of angiogenesis is one of the major adaptive mechanisms to counteract the adverse effects of hypoxia. In a previous work, we have shown that the adult rat striatum promotes angiogenesis in response to hypoxia via upregulation of the most important proangiogenic factor, the vascular endothelial growth factor (VEGF). However, the effects of hypoxia on angiogenesis in the aged striatum remain unknown and constitute our aim. Here we show the upregulation of hypoxia-inducible factor-1α in the striatum of aged (24-25 months old) Wistar rats exposed to acute hypoxia and analysed during a reoxygenation period ranging from 0 h to 5 days. While the mRNA expression of the proangiogenic factors VEGF, transforming growth factor-β1 (TGF-β1), and adrenomedullin dropped at 0 h post-hypoxia compared to normoxic control, no changes were detected at the protein level, showing an impaired response of these proangiogenic factors to hypoxia in the aged striatum. However, the striatal blood vessel network increased at 24 h of reoxygenation, suggesting that mechanisms independent from these proangiogenic factors may be involved in hypoxia-induced angiogenesis in the striatum of aged rats. A thorough understanding of the factors involved in the response to hypoxia is essential to guide the design of therapies for hypoxia-related diseases in the aged brain.
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Affiliation(s)
- Francisco Molina
- Department of Health Science, University of Jaén, Paraje Las Lagunillas s/n, 23071, Jaén, Spain
| | - M Luisa Del Moral
- Department of Experimental Biology, University of Jaén, Paraje Las Lagunillas s/n, 23071, Jaén, Spain
| | - M Ángeles Peinado
- Department of Experimental Biology, University of Jaén, Paraje Las Lagunillas s/n, 23071, Jaén, Spain
| | - Alma Rus
- Department of Cell Biology, University of Granada, Avenida de la Fuentenueva s/n, 18071, Granada, Spain.
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Menon RT, Shrestha AK, Shivanna B. Hyperoxia exposure disrupts adrenomedullin signaling in newborn mice: Implications for lung development in premature infants. Biochem Biophys Res Commun 2017; 487:666-671. [PMID: 28438602 DOI: 10.1016/j.bbrc.2017.04.112] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Accepted: 04/20/2017] [Indexed: 11/25/2022]
Abstract
Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD), a chronic lung disease of human infants that is characterized by disrupted lung angiogenesis. Adrenomedullin (AM) is a multifunctional peptide with angiogenic and vasoprotective properties. AM signals via its cognate receptors, calcitonin receptor-like receptor (Calcrl) and receptor activity-modifying protein 2 (RAMP2). Whether hyperoxia affects the pulmonary AM signaling pathway in neonatal mice and whether AM promotes lung angiogenesis in human infants are unknown. Therefore, we tested the following hypotheses: (1) hyperoxia exposure will disrupt AM signaling during the lung development period in neonatal mice; and (2) AM will promote angiogenesis in fetal human pulmonary artery endothelial cells (HPAECs) via extracellular signal-regulated kinases (ERK) 1/2 activation. We initially determined AM, Calcrl, and RAMP2 mRNA levels in mouse lungs on postnatal days (PND) 3, 7, 14, and 28. Next we determined the mRNA expression of these genes in neonatal mice exposed to hyperoxia (70% O2) for up to 14 d. Finally, using HPAECs, we evaluated if AM activates ERK1/2 and promotes tubule formation and cell migration. Lung AM, Calcrl, and RAMP2 mRNA expression increased from PND 3 and peaked at PND 14, a time period during which lung development occurs in mice. Interestingly, hyperoxia exposure blunted this peak expression in neonatal mice. In HPAECs, AM activated ERK1/2 and promoted tubule formation and cell migration. These findings support our hypotheses, emphasizing that AM signaling axis is a potential therapeutic target for human infants with BPD.
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Affiliation(s)
- Renuka T Menon
- Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, United States
| | - Amrit Kumar Shrestha
- Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, United States
| | - Binoy Shivanna
- Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, United States.
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22
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Imai A, Toriyama Y, Iesato Y, Hirabayashi K, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Liu T, Xian X, Zhai L, Dai K, Tanimura K, Liu T, Cui N, Yamauchi A, Murata T, Shindo T. Adrenomedullin Suppresses Vascular Endothelial Growth Factor-Induced Vascular Hyperpermeability and Inflammation in Retinopathy. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:999-1015. [PMID: 28322199 DOI: 10.1016/j.ajpath.2017.01.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 01/19/2017] [Indexed: 11/29/2022]
Abstract
Diabetic macular edema (DME) is caused by blood-retinal barrier breakdown associated with retinal vascular hyperpermeability and inflammation, and it is the major cause of visual dysfunction in diabetic retinopathy. Adrenomedullin (ADM) is an endogenous peptide first identified as a strong vasodilator. ADM is expressed in the eyes and is up-regulated in various eye diseases, although the pathophysiological significance is largely unknown. We investigated the effect of ADM on DME. In Kimba mice, which overexpress human vascular endothelial growth factor in their retinas, the capillary dropout, vascular leakage, and vascular fragility characteristic of diabetic retinopathy were observed. Intravitreal or systemic administration of ADM to Kimba mice ameliorated both the capillary dropout and vascular leakage. Evaluation of the transendothelial electrical resistance and fluorescein isothiocyanate-dextran permeability of an endothelial cell monolayer using TR-iBRB retinal capillary endothelial cells revealed that vascular endothelial growth factor enhanced vascular permeability but that co-administration of ADM suppressed the effect, in part by enhancing tight junction formation between endothelial cells. In addition, a comprehensive PCR array analysis showed that ADM administration suppressed various molecules related to inflammation and NF-κB signaling within retinas. From these results, we suggest that by exerting inhibitory effects on retinal inflammation, vascular permeability, and blood-retinal barrier breakdown, ADM could serve as a novel therapeutic agent for the treatment of DME.
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Affiliation(s)
- Akira Imai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Yuichi Toriyama
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Yasuhiro Iesato
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Kazutaka Hirabayashi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Takayuki Sakurai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Akiko Kamiyoshi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Yuka Ichikawa-Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Hisaka Kawate
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Megumu Tanaka
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Tian Liu
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Xian Xian
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Liuyu Zhai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Kun Dai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Keiya Tanimura
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Teng Liu
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Nanqi Cui
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | | | - Toshinori Murata
- Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Takayuki Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
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23
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Cheng L, Yu H, Yan N, Lai K, Xiang M. Hypoxia-Inducible Factor-1α Target Genes Contribute to Retinal Neuroprotection. Front Cell Neurosci 2017; 11:20. [PMID: 28289375 PMCID: PMC5326762 DOI: 10.3389/fncel.2017.00020] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Accepted: 01/23/2017] [Indexed: 02/05/2023] Open
Abstract
Hypoxia-inducible factor (HIF) is a transcription factor that facilitates cellular adaptation to hypoxia and ischemia. Long-standing evidence suggests that one isotype of HIF, HIF-1α, is involved in the pathogenesis of various solid tumors and cardiac diseases. However, the role of HIF-1α in retina remains poorly understood. HIF-1α has been recognized as neuroprotective in cerebral ischemia in the past two decades. Additionally, an increasing number of studies has shown that HIF-1α and its target genes contribute to retinal neuroprotection. This review will focus on recent advances in the studies of HIF-1α and its target genes that contribute to retinal neuroprotection. A thorough understanding of the function of HIF-1α and its target genes may lead to identification of novel therapeutic targets for treating degenerative retinal diseases including glaucoma, age-related macular degeneration, diabetic retinopathy, and retinal vein occlusions.
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Affiliation(s)
- Lin Cheng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University Guangzhou, China
| | - Honghua Yu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen UniversityGuangzhou, China; Department of Ophthalmology, General Hospital of Guangzhou Military Command of PLAGuangzhou, China
| | - Naihong Yan
- Department of Ophthalmology and Ophthalmic Laboratories, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University Chengdu, China
| | - Kunbei Lai
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University Guangzhou, China
| | - Mengqing Xiang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen UniversityGuangzhou, China; Center for Advanced Biotechnology and Medicine and Department of Pediatrics, Rutgers University-Robert Wood Johnson Medical SchoolPiscataway, NJ, USA
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24
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Wang X, Lockhart SM, Rathjen T, Albadawi H, Sørensen D, O'Neill BT, Dwivedi N, Preil SR, Beck HC, Dunwoodie SL, Watkins MT, Rasmussen LM, Rask-Madsen C. Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells. Diabetes 2016; 65:3680-3690. [PMID: 27561725 PMCID: PMC5127242 DOI: 10.2337/db16-0001] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2016] [Accepted: 08/15/2016] [Indexed: 12/17/2022]
Abstract
In patients with atherosclerotic complications of diabetes, impaired neovascularization of ischemic tissue in the myocardium and lower limb limits the ability of these tissues to compensate for poor perfusion. We identified 10 novel insulin-regulated genes, among them Adm, Cited2, and Ctgf, which were downregulated in endothelial cells by insulin through FoxO1. CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2), which was downregulated by insulin by up to 54%, is an important negative regulator of hypoxia-inducible factor (HIF) and impaired HIF signaling is a key mechanism underlying the impairment of angiogenesis in diabetes. Consistent with impairment of vascular insulin action, CITED2 was increased in cardiac endothelial cells from mice with diet-induced obesity and from db/db mice and was 3.8-fold higher in arterial tissue from patients with type 2 diabetes than control subjects without diabetes. CITED2 knockdown promoted endothelial tube formation and endothelial cell proliferation, whereas CITED2 overexpression impaired HIF activity in vitro. After femoral artery ligation, induction of an endothelial-specific HIF target gene in hind limb muscle was markedly upregulated in mice with endothelial cell deletion of CITED2, suggesting that CITED2 can limit HIF activity in vivo. We conclude that vascular insulin resistance in type 2 diabetes contributes to the upregulation of CITED2, which impairs HIF signaling and endothelial proangiogenic function.
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Affiliation(s)
- Xuanchun Wang
- Joslin Diabetes Center and Harvard Medical School, Boston, MA
- Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Samuel M Lockhart
- Joslin Diabetes Center and Harvard Medical School, Boston, MA
- Queen's University Belfast, Belfast, U.K
| | - Thomas Rathjen
- Joslin Diabetes Center and Harvard Medical School, Boston, MA
- Novo Nordisk A/S, Måløv, Denmark
| | - Hassan Albadawi
- Department of Surgery, Massachusetts General Hospital, Boston, MA
| | - Ditte Sørensen
- Joslin Diabetes Center and Harvard Medical School, Boston, MA
- University of Southern Denmark, Odense, Denmark
- Danish Diabetes Academy, Odense, Denmark
| | - Brian T O'Neill
- Joslin Diabetes Center and Harvard Medical School, Boston, MA
| | - Nishant Dwivedi
- Joslin Diabetes Center and Harvard Medical School, Boston, MA
| | - Simone R Preil
- Center for Individualized Medicine of Arterial Diseases (CIMA), Odense University Hospital, Odense, Denmark
| | - Hans Christian Beck
- Center for Individualized Medicine of Arterial Diseases (CIMA), Odense University Hospital, Odense, Denmark
| | - Sally L Dunwoodie
- Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
- St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
- School of Molecular Bioscience, University of Sydney, Sydney, New South Wales, Australia
| | | | - Lars Melholt Rasmussen
- Center for Individualized Medicine of Arterial Diseases (CIMA), Odense University Hospital, Odense, Denmark
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25
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Tanaka M, Koyama T, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Liu T, Xian X, Imai A, Zhai L, Hirabayashi K, Owa S, Yamauchi A, Igarashi K, Taniguchi S, Shindo T. The endothelial adrenomedullin-RAMP2 system regulates vascular integrity and suppresses tumour metastasis. Cardiovasc Res 2016; 111:398-409. [PMID: 27307317 DOI: 10.1093/cvr/cvw166] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 06/11/2016] [Indexed: 11/13/2022] Open
Abstract
AIMS Controlling vascular integrity is expected to be a novel therapeutic target of cancers as well as cardiovascular diseases. Adrenomedullin (AM) and its receptor-modulating protein, RAMP2, have been identified as essential mediators of cardiovascular homeostasis. In this study, we used inducible vascular endothelial cell-specific RAMP2 knockout (DI-E-RAMP2(-/-)) mice to clarify the contribution made by the endogenous AM-RAMP2 system to angiogenesis and metastasis. METHODS AND RESULTS Subcutaneously transplanted sarcoma or melanoma cells showed less growth and angiogenesis in DI-E-RAMP2(-/-) than in control mice. On the other hand, after the transplantation of B16BL6 melanoma cells into hindlimb footpads, spontaneous metastasis to the lung was enhanced in DI-E-RAMP2(-/-) mice. Early after RAMP2 gene deletion, DI-E-RAMP2(-/-) mice showed enhanced vascular permeability, endothelial-mesenchymal transition (EndMT)-like change, and systemic oedema. Within the lungs of DI-E-RAMP2(-/-) mice, pulmonary endothelial cells were deformed, and inflammatory cells infiltrated the vessel walls and expressed the chemotactic factors S100A8/9 and SAA3, which attract tumour cells and mediate the formation of a pre-metastatic niche. Conversely, the overexpression of RAMP2 suppressed tumour cell adhesion to endothelial cells, tumour metastasis, and improved survival. CONCLUSION These findings indicate that the AM-RAMP2 system regulates vascular integrity, whereas RAMP2 deletion promotes vascular permeability and EndMT-like change within primary lesions and formation of pre-metastatic niches in distant organs by destabilizing the vascular structure and inducing inflammation. Vascular integrity regulated by the AM-RAMP2 system could thus be a hopeful therapeutic target for suppressing tumour metastasis.
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Affiliation(s)
- Megumu Tanaka
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
| | - Teruhide Koyama
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
| | - Takayuki Sakurai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
| | - Akiko Kamiyoshi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
| | - Yuka Ichikawa-Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
| | - Hisaka Kawate
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
| | - Tian Liu
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
| | - Xian Xian
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
| | - Akira Imai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
| | - Liuyu Zhai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
| | - Kazutaka Hirabayashi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
| | - Shinji Owa
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
| | - Akihiro Yamauchi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
| | - Kyoko Igarashi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
| | - Shun'ichiro Taniguchi
- Department of Molecular Oncology, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
| | - Takayuki Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
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26
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Adrenomedullin: A potential therapeutic target for retinochoroidal disease. Prog Retin Eye Res 2016; 52:112-29. [DOI: 10.1016/j.preteyeres.2016.01.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 01/06/2016] [Accepted: 01/07/2016] [Indexed: 11/22/2022]
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27
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Yoshizawa T, Takizawa S, Shimada S, Tokudome T, Shindo T, Matsumoto K. Effects of Adrenomedullin on Doxorubicin-Induced Cardiac Damage in Mice. Biol Pharm Bull 2016; 39:737-46. [PMID: 26902282 DOI: 10.1248/bpb.b15-00832] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Doxorubicin (DOX) is one of the best known anticancer drugs, and is used in the treatment of lymphoma, lung cancer, stomach cancer, and a number of other cancers. However, DOX has some serious side effects, the worst being lethal heart failure. Occasionally, its side effects result in the cessation of the anticancer treatment, thus having a serious adverse influence on prognosis. Agents that can be administered as alternative prophylactics or to ameliorate the side effects of DOX will be useful in increasing the safety and efficacy of anticancer therapy. Adrenomedullin (AM) is a peptide hormone secreted by many organs, including the heart; it has an organ-protective effect, including antiapoptotic, anti-inflammatory, and antioxidative stress. Blood AM levels increase with heart failure; endogenic AM has been suggested in order to protect the heart. Furthermore, exogenous AM administration has shown therapeutic effects for heart failure in patients. However, it is unclear whether AM can protect the heart against drug-induced cardiac injury in vivo. The present study was performed in order to investigate the effects of AM on DOX-induced cardiac damage. Male BALB/c mice were treated with DOX and/or AM. Exogenous AM improved the survival ratio of DOX-treated mice. In addition, AM reduced serum lactate dehydrogenase (LDH) levels following DOX treatment. On pathological examination, AM was shown to inhibit DOX-induced cardiac tissue damage, mitochondrial abnormality, and cell death. These findings suggest that AM has a protective effect against DOX-induced cardiac damage.
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Affiliation(s)
- Takahiro Yoshizawa
- Research Center for Human and Environmental Sciences, Shinshu University
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28
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Kato J, Kitamura K. Bench-to-bedside pharmacology of adrenomedullin. Eur J Pharmacol 2015; 764:140-148. [PMID: 26144371 DOI: 10.1016/j.ejphar.2015.06.061] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Revised: 06/24/2015] [Accepted: 06/30/2015] [Indexed: 01/01/2023]
Abstract
The bioactive peptide adrenomedullin (AM) exerts pleiotropic actions in various organs and tissues. In the heart, AM has an inhibitory effect on ventricular remodeling, suppressing cardiomyocyte hypertrophy and the proliferation of cardiac fibroblasts. This pharmacological property was shown not only in rat models of acute myocardial infarction, but also clinically in patients with this cardiac disease. An originally characterized feature of AM was a potent vasodilatory effect, but this peptide was found to be important for vascular integrity and angiogenesis. AM-induced angiogenesis is involved in tumor growth, while AM inhibits apoptosis of some types of tumor cell. A unique pharmacological property is anti-inflammatory activity, which has been characterized in sepsis and inflammatory bowel diseases; thus, there is an ongoing clinical trial to test the efficacy of AM for patients with intractable ulcerative colitis. These activities are assumed to be mediated via the specific receptor formed by calcitonin receptor-like receptor and receptor activity-modifying protein 2 or 3, while some questions remain to be answered about the molecular mechanisms of this signal transduction system. Taking these findings together, AM is a bioactive peptide with pleiotropic effects, with potential as a therapeutic tool for a wide range of human diseases from myocardial infarction to malignant tumors or inflammatory bowel diseases.
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Affiliation(s)
- Johji Kato
- Frontier Science Research Center, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan.
| | - Kazuo Kitamura
- Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan
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29
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Toriyama Y, Iesato Y, Imai A, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Yamauchi A, Igarashi K, Tanaka M, Liu T, Xian X, Zhai L, Owa S, Murata T, Shindo T. Pathophysiological Function of Endogenous Calcitonin Gene–Related Peptide in Ocular Vascular Diseases. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:1783-94. [DOI: 10.1016/j.ajpath.2015.02.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 02/24/2015] [Accepted: 02/26/2015] [Indexed: 10/23/2022]
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30
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Koyama T, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Shindo T. Adrenomedullin-RAMP2 System in Vascular Endothelial Cells. J Atheroscler Thromb 2015; 22:647-53. [DOI: 10.5551/jat.29967] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Affiliation(s)
- Teruhide Koyama
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine
| | - Takayuki Sakurai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine
| | - Akiko Kamiyoshi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine
| | - Yuka Ichikawa-Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine
| | - Hisaka Kawate
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine
| | - Takayuki Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine
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31
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Larráyoz IM, Martínez-Herrero S, García-Sanmartín J, Ochoa-Callejero L, Martínez A. Adrenomedullin and tumour microenvironment. J Transl Med 2014; 12:339. [PMID: 25475159 PMCID: PMC4272513 DOI: 10.1186/s12967-014-0339-2] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 11/21/2014] [Indexed: 01/03/2023] Open
Abstract
Adrenomedullin (AM) is a regulatory peptide whose involvement in tumour progression is becoming more relevant with recent studies. AM is produced and secreted by the tumour cells but also by numerous stromal cells including macrophages, mast cells, endothelial cells, and vascular smooth muscle cells. Most cancer patients present high levels of circulating AM and in some cases these higher levels correlate with a worst prognosis. In some cases it has been shown that the high AM levels return to normal following surgical removal of the tumour, thus indicating the tumour as the source of this excessive production of AM. Expression of this peptide is a good investment for the tumour cell since AM acts as an autocrine/paracrine growth factor, prevents apoptosis-mediated cell death, increases tumour cell motility and metastasis, induces angiogenesis, and blocks immunosurveillance by inhibiting the immune system. In addition, AM expression gets rapidly activated by hypoxia through a HIF-1α mediated mechanism, thus characterizing AM as a major survival factor for tumour cells. Accordingly, a number of studies have shown that inhibition of this peptide or its receptors results in a significant reduction in tumour progression. In conclusion, AM is a great target for drug development and new drugs interfering with this system are being developed.
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Affiliation(s)
- Ignacio M Larráyoz
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
| | - Sonia Martínez-Herrero
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
| | - Josune García-Sanmartín
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
| | - Laura Ochoa-Callejero
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
| | - Alfredo Martínez
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
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32
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Siclari VA, Mohammad KS, Tompkins DR, Davis H, McKenna CR, Peng X, Wessner LL, Niewolna M, Guise TA, Suvannasankha A, Chirgwin JM. Tumor-expressed adrenomedullin accelerates breast cancer bone metastasis. Breast Cancer Res 2014; 16:458. [PMID: 25439669 PMCID: PMC4303191 DOI: 10.1186/s13058-014-0458-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 10/09/2014] [Indexed: 01/23/2023] Open
Abstract
Introduction Adrenomedullin (AM) is secreted by breast cancer cells and increased by hypoxia. It is a multifunctional peptide that stimulates angiogenesis and proliferation. The peptide is also a potent paracrine stimulator of osteoblasts and bone formation, suggesting a role in skeletal metastases—a major site of treatment-refractory tumor growth in patients with advanced disease. Methods The role of adrenomedullin in bone metastases was tested by stable overexpression in MDA-MB-231 breast cancer cells, which cause osteolytic bone metastases in a standard animal model. Cells with fivefold increased expression of AM were characterized in vitro, inoculated into immunodeficient mice and compared for their ability to form bone metastases versus control subclones. Bone destruction was monitored by X-ray, and tumor burden and osteoclast numbers were determined by quantitative histomorphometry. The effects of AM overexpression on tumor growth and angiogenesis in the mammary fat pad were determined. The effects of AM peptide on osteoclast-like multinucleated cell formation were tested in vitro. A small-molecule AM antagonist was tested for its effects on AM-stimulated ex vivo bone cell cultures and co-cultures with tumor cells, where responses of tumor and bone were distinguished by species-specific real-time PCR. Results Overexpression of AM mRNA did not alter cell proliferation in vitro, expression of tumor-secreted factors or cell cycle progression. AM-overexpressing cells caused osteolytic bone metastases to develop more rapidly, which was accompanied by decreased survival. In the mammary fat pad, tumors grew more rapidly with unchanged blood vessel formation. Tumor growth in the bone was also more rapid, and osteoclasts were increased. AM peptide potently stimulated bone cultures ex vivo; responses that were blocked by small-molecule adrenomedullin antagonists in the absence of cellular toxicity. Antagonist treatment dramatically suppressed tumor growth in bone and decreased markers of osteoclast activity. Conclusions The results identify AM as a target for therapeutic intervention against bone metastases. Adrenomedullin potentiates osteolytic responses in bone to metastatic breast cancer cells. Small-molecule antagonists can effectively block bone-mediated responses to tumor-secreted adrenomedullin, and such agents warrant development for testing in vivo. Electronic supplementary material The online version of this article (doi:10.1186/s13058-014-0458-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Valerie A Siclari
- Department of Biochemistry and Molecular Genetics, University of Virginia, PO Box 800733, Charlottesville, VA, 22908, USA.
| | - Khalid S Mohammad
- Division of Endocrinology and Metabolism, Department of Medicine, 450 Ray C Hunt Dr, University of Virginia, PO Box 801406, Charlottesville, VA, 22908, USA. .,Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, 980 Walnut, St, C321-C, Indianapolis, IN, 46202, USA.
| | - Douglas R Tompkins
- Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, 980 Walnut, St, C321-C, Indianapolis, IN, 46202, USA. .,Richard L. Roudebush VA Medical Center, 1481 W 10th St, Indianapolis, IN, 46202, USA.
| | - Holly Davis
- Division of Endocrinology and Metabolism, Department of Medicine, 450 Ray C Hunt Dr, University of Virginia, PO Box 801406, Charlottesville, VA, 22908, USA.
| | - C Ryan McKenna
- Division of Endocrinology and Metabolism, Department of Medicine, 450 Ray C Hunt Dr, University of Virginia, PO Box 801406, Charlottesville, VA, 22908, USA.
| | - Xianghong Peng
- Division of Endocrinology and Metabolism, Department of Medicine, 450 Ray C Hunt Dr, University of Virginia, PO Box 801406, Charlottesville, VA, 22908, USA. .,Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, 980 Walnut, St, C321-C, Indianapolis, IN, 46202, USA.
| | - Lisa L Wessner
- Division of Endocrinology and Metabolism, Department of Medicine, 450 Ray C Hunt Dr, University of Virginia, PO Box 801406, Charlottesville, VA, 22908, USA.
| | - Maria Niewolna
- Division of Endocrinology and Metabolism, Department of Medicine, 450 Ray C Hunt Dr, University of Virginia, PO Box 801406, Charlottesville, VA, 22908, USA. .,Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, 980 Walnut, St, C321-C, Indianapolis, IN, 46202, USA.
| | - Theresa A Guise
- Division of Endocrinology and Metabolism, Department of Medicine, 450 Ray C Hunt Dr, University of Virginia, PO Box 801406, Charlottesville, VA, 22908, USA. .,Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, 980 Walnut, St, C321-C, Indianapolis, IN, 46202, USA.
| | - Attaya Suvannasankha
- Richard L. Roudebush VA Medical Center, 1481 W 10th St, Indianapolis, IN, 46202, USA. .,Division of Hematology/Oncology, Department of Medicine, 980 Walnut St, C321-H, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
| | - John M Chirgwin
- Department of Biochemistry and Molecular Genetics, University of Virginia, PO Box 800733, Charlottesville, VA, 22908, USA. .,Division of Endocrinology and Metabolism, Department of Medicine, 450 Ray C Hunt Dr, University of Virginia, PO Box 801406, Charlottesville, VA, 22908, USA. .,Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, 980 Walnut, St, C321-C, Indianapolis, IN, 46202, USA. .,Richard L. Roudebush VA Medical Center, 1481 W 10th St, Indianapolis, IN, 46202, USA.
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Igarashi K, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Yamauchi A, Toriyama Y, Tanaka M, Liu T, Xian X, Imai A, Zhai L, Owa S, Koyama T, Uetake R, Ihara M, Shindo T. Pathophysiological roles of adrenomedullin-RAMP2 system in acute and chronic cerebral ischemia. Peptides 2014; 62:21-31. [PMID: 25252154 DOI: 10.1016/j.peptides.2014.08.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 08/25/2014] [Accepted: 08/25/2014] [Indexed: 11/20/2022]
Abstract
The accessory protein RAMP2 is a component of the CLR/RAMP2 dimeric adrenomedullin (AM) receptor and is the primary determinant of the vascular functionality of AM. RAMP2 is highly expressed in the brain; however, its function there remains unclear. We therefore used heterozygous RAMP2 knockout (RAMP2+/-) mice, in which RAMP2 expression was reduced by half, to examine the actions of the endogenous AM-RAMP2 system in cerebral ischemia. To induce acute or chronic ischemia, mice were subjected to middle cerebral artery occlusion (MCAO) or bilateral common carotid artery stenosis (BCAS), respectively. In RAMP2+/- mice subjected to MCAO, recovery of cerebral blood flow (CBF) was slower than in WT mice. AM gene expression was upregulated after infarction in both genotypes, but the increase was greater in RAMP2+/- mice. Pathological analysis revealed severe nerve cell death and demyelination, and a higher level of oxidative stress in RAMP2+/- mice. In RAMP2+/- mice subjected to BCAS, recovery of cerebral perfusion was slower and less complete than in WT mice. In an 8-arm radial maze test, RAMP2+/- mice required more time to solve the maze and showed poorer reference memory. They also showed greater reductions in nerve cells and less compensatory capillary growth than WT mice. These results indicate the AM-RAMP2 system works to protect nerve cells from both acute and chronic cerebral ischemia by maintaining CBF, suppressing oxidative stress, and in the case of chronic ischemia, enhancing capillary growth.
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Affiliation(s)
- Kyoko Igarashi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Takayuki Sakurai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Akiko Kamiyoshi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Yuka Ichikawa-Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Hisaka Kawate
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Akihiro Yamauchi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Yuichi Toriyama
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Megumu Tanaka
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Tian Liu
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Xian Xian
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Akira Imai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Liuyu Zhai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Shinji Owa
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Teruhide Koyama
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Ryuichi Uetake
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Masafumi Ihara
- Department of Regenerative Medicine, Research Institute of Biomedical Research and Innovation, Kobe, Japan
| | - Takayuki Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
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Yamauchi A, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Igarashi K, Toriyama Y, Tanaka M, Liu T, Xian X, Imai A, Zhai L, Owa S, Arai T, Shindo T. Functional differentiation of RAMP2 and RAMP3 in their regulation of the vascular system. J Mol Cell Cardiol 2014; 77:73-85. [DOI: 10.1016/j.yjmcc.2014.09.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Revised: 09/12/2014] [Accepted: 09/15/2014] [Indexed: 01/08/2023]
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Suzuki E, Nishimatsu H, Homma Y. Stem cell therapy for erectile dysfunction. World J Clin Urol 2014; 3:272-282. [DOI: 10.5410/wjcu.v3.i3.272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 05/03/2014] [Accepted: 10/10/2014] [Indexed: 02/06/2023] Open
Abstract
Erectile dysfunction (ED) is an important health problem that has commonly been clinically treated using phosphodiesterase type 5 inhibitors (PDE5Is). However, PDE5Is are less effective when the structure of the cavernous body has been severely injured, and thus regeneration is required. Stem cell therapy has been investigated as a possible means for regenerating the injured cavernous body. Stem cells are classified into embryonic stem cells and adult stem cells (ASCs), and the intracavernous injection of ASCs has been explored as a therapy in animal ED models. Bone marrow-derived mesenchymal stem cells and adipose tissue-derived stem cells are major sources of ASCs used for the treatment of ED, and accumulated evidence now suggests that ASCs are useful in the restoration of erectile function and the regeneration of the cavernous body. However, the mechanisms by which ASCs recover erectile function remain controversial. Some studies indicated that ASCs were differentiated into the vascular endothelial cells, vascular smooth muscle cells, and nerve cells that originally resided in the cavernous body, whereas other studies have suggested that ASCs improved erectile function via the secretion of anti-apoptotic and/or proangiogenic cytokines rather than differentiation into other cell types. In this paper, we reviewed the characteristics of stem cells used for the treatment of ED, and the possible mechanisms by which these cells exert their effects. We also discussed the problems to be solved before implementation in the clinical setting.
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Allen J, Howell K. Microvascular imaging: techniques and opportunities for clinical physiological measurements. Physiol Meas 2014; 35:R91-R141. [DOI: 10.1088/0967-3334/35/7/r91] [Citation(s) in RCA: 131] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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Shindo T, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Koyama T. [Pathophysiological roles of adrenomedullin and its receptor activity modifying system]. Nihon Yakurigaku Zasshi 2014; 143:232-235. [PMID: 24813793 DOI: 10.1254/fpj.143.232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
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Adrenomedullin-RAMP2 system suppresses ER stress-induced tubule cell death and is involved in kidney protection. PLoS One 2014; 9:e87667. [PMID: 24505304 PMCID: PMC3914859 DOI: 10.1371/journal.pone.0087667] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2013] [Accepted: 12/29/2013] [Indexed: 11/19/2022] Open
Abstract
Various bioactive peptides have been implicated in the homeostasis of organs and tissues. Adrenomedullin (AM) is a peptide with various bioactivities. AM-receptor, calcitonin-receptor-like receptor (CLR) associates with one of the subtypes of the accessory proteins, RAMPs. Among the RAMP subisoforms, only RAMP2 knockout mice (−/−) reproduce the phenotype of embryonic lethality of AM−/−, illustrating the importance of the AM-RAMP2-signaling system. Although AM and RAMP2 are abundantly expressed in kidney, their function there remains largely unknown. We used genetically modified mice to assess the pathophysiological functions of the AM-RAMP2 system. RAMP2+/− mice and their wild-type littermates were used in a streptozotocin (STZ)-induced renal injury model. The effect of STZ on glomeruli did not differ between the 2 types of mice. On the other hand, damage to the proximal urinary tubules was greater in RAMP2+/−. Tubular injury in RAMP2+/− was resistant to correction of blood glucose by insulin administration. We examined the effect of STZ on human renal proximal tubule epithelial cells (RPTECs), which express glucose transporter 2 (GLUT2), the glucose transporter that specifically takes up STZ. STZ activated the endoplasmic reticulum (ER) stress sensor protein kinase RNA-like endoplasmic reticulum kinase (PERK). AM suppressed PERK activation, its downstream signaling, and CCAAT/enhancer-binding homologous protein (CHOP)-induced cell death. We confirmed that the tubular damage was caused by ER stress-induced cell death using tunicamycin (TUN), which directly evokes ER stress. In RAMP2+/− kidneys, TUN caused severe injury with enhanced ER stress. In wild-type mice, TUN-induced tubular damage was reversed by AM administration. On the other hand, in RAMP2+/−, the rescue effect of exogenous AM was lost. These results indicate that the AM-RAMP2 system suppresses ER stress-induced tubule cell death, thereby exerting a protective effect on kidney. The AM-RAMP2 system thus has the potential to serve as a therapeutic target in kidney disease.
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Sato T, Takahashi M, Fujita D, Oba S, Nishimatsu H, Nagano T, Suzuki E. Adipose-Derived Stem Cells Stimulate Reendothelialization in Stented Rat Abdominal Aorta. Circ J 2014; 78:1762-9. [DOI: 10.1253/circj.cj-13-1579] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Tomohiko Sato
- Department of Internal Medicine, Faculty of Medicine, University of Tokyo
| | - Masao Takahashi
- Department of Internal Medicine, Faculty of Medicine, University of Tokyo
| | - Daishi Fujita
- Department of Internal Medicine, Faculty of Medicine, University of Tokyo
| | - Shigeyoshi Oba
- Department of Internal Medicine, Faculty of Medicine, University of Tokyo
| | | | - Tetsuo Nagano
- Graduate School of Pharmaceutical Sciences, University of Tokyo
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Wang L, Gala M, Yamamoto M, Pino MS, Kikuchi H, Shue DS, Shirasawa S, Austin TR, Lynch MP, Rueda BR, Zukerberg LR, Chung DC. Adrenomedullin is a therapeutic target in colorectal cancer. Int J Cancer 2013; 134:2041-50. [PMID: 24519534 DOI: 10.1002/ijc.28542] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Accepted: 09/27/2013] [Indexed: 12/17/2022]
Abstract
The KRAS oncogene influences angiogenesis, metastasis and chemoresistance in colorectal cancers (CRCs), and these processes are all enhanced in hypoxic conditions. To define functional activities of mutant KRAS in a hypoxic microenvironment, we first performed cDNA microarray experiments in isogenic DKs5 and DKO3 colon cancer cell lines that differ only by their expression of mutant KRAS (K-ras(D13)). Adrenomedullin (ADM) was identified as one of the most significantly upregulated genes in DKs5 cells that express the KRAS oncogene in hypoxia (3.2-fold, p = 1.47 × 10(-5)). Ectopic expression of mutant KRAS (K-ras(V12)) in Caco-2 cells (K-ras(WT)) induced ADM, whereas selective knockdown of mutant KRAS alleles (K-ras(D13) or K-ras(V12)) in HCT116, DLD1 and SW480 colon cancer cells suppressed the expression of ADM in hypoxia. Knockdown of ADM in colon tumor xenografts blocked angiogenesis and stimulated apoptosis, resulting in tumor suppression. Furthermore, ADM also regulated colon cancer cell invasion in vitro. Among 56 patients with CRC, significantly higher expression levels of ADM were observed in samples harboring a KRAS mutation. Collectively, ADM is a new target of oncogenic KRAS in the setting of hypoxia. This observation suggests that therapeutic targets may differ depending upon the specific tumor microenvironment.
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Affiliation(s)
- Liangjing Wang
- Gastrointestinal Unit Massachusetts General Hospital, Harvard Medical School, Boston, MA; Department of Gastroenterology Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Miyamoto N, Pham LDD, Seo JH, Kim KW, Lo EH, Arai K. Crosstalk between cerebral endothelium and oligodendrocyte. Cell Mol Life Sci 2013; 71:1055-66. [PMID: 24132511 DOI: 10.1007/s00018-013-1488-9] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Revised: 09/12/2013] [Accepted: 09/30/2013] [Indexed: 01/19/2023]
Abstract
It is now relatively well accepted that the cerebrovascular system does not merely provide inert pipes for blood delivery to the brain. Cerebral endothelial cells may compose an embedded bunker of trophic factors that contribute to brain homeostasis and function. Recent findings suggest that soluble factors from cerebral endothelial cells nourish neighboring cells, such as neurons and astrocytes. Although data are strongest in supporting mechanisms of endothelial-neuron and/or endothelial-astrocyte trophic coupling, it is likely that similar interactions also exist between cerebral endothelial cells and oligodendrocyte lineage cells. In this mini-review, we summarize current advances in the field of endothelial-oligodendrocyte trophic coupling. These endothelial-oligodendrocyte interactions may comprise the oligovascular niche to maintain their cellular functions and sustain ongoing angiogenesis/oligodendrogenesis. Importantly, it should be noted that the cell-cell interactions are not static-the trophic coupling is disturbed under acute phase after brain injury, but would be recovered in the chronic phase to promote brain remodeling and repair. Oligodendrocyte lineage cells play critical roles in white matter function, and under pathological conditions, oligodendrocyte dysfunction lead to white matter damage. Therefore, a deeper understanding of the mechanisms of endothelial-oligodendrocyte trophic coupling may lead to new therapeutic approaches for white matter-related diseases, such as stroke or vascular dementia.
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Affiliation(s)
- Nobukazu Miyamoto
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, MGH East 149-2401, Charlestown, MA, 02129, USA
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Targeting tumor micro-environment for design and development of novel anti-angiogenic agents arresting tumor growth. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2013; 113:333-54. [PMID: 24139944 DOI: 10.1016/j.pbiomolbio.2013.10.001] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2013] [Revised: 10/05/2013] [Accepted: 10/08/2013] [Indexed: 12/12/2022]
Abstract
Angiogenesis: a process of generation of new blood vessels has been proved to be necessary for sustained tumor growth and cancer progression. Inhibiting angiogenesis pathway has long been remained a significant hope for the development of novel, effective and target orientated antitumor agents arresting the tumor proliferation and metastasis. The process of neoangiogenesis as a biological process is regulated by several pro- and anti-angiogenic factors, especially vascular endothelial growth factor, fibroblast growth factor, epidermal growth factor, hypoxia inducible factor 1 and transforming growth factor. Every endothelial cell destined for vessel formation is equipped with receptors for these angiogenic peptides. Moreover, numerous other angiogenic cytokines such as platelet derived growth factor (PGDF), placenta growth factor (PGF), nerve growth factor (NGF), stem-cell factor (SCF), and interleukins-2, 4, 6 etc. These molecular players performs critical role in regulating the angiogenic switch. Couple of decade's research in molecular aspects of tumor biology has unraveled numerous structural and functional mysteries of these angiogenic peptides. In present article, a detailed update on the functional and structural peculiarities of the various angiogenic peptides is described focusing on structural opportunities made available that has potential to be used to modulate function of these angiogenic peptides in developing therapeutic agents targeting neoplastic angiogenesis. The data may be useful in the mainstream of developing novel anticancer agents targeting tumor angiogenesis. We also discuss major therapeutic agents that are currently used in angiogenesis associated therapies as well as those are subject of active research or are in clinical trials.
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Nishimatsu H, Suzuki E, Nomiya A, Niimi A, Suzuki M, Fujimura T, Fukuhara H, Homma Y. Adrenomedullin and angiopoietin-1 additively restore erectile function in diabetic rats: comparison with the combination therapy of vascular endothelial growth factor and angiopoietin-1. J Sex Med 2013; 10:1707-19. [PMID: 23651347 DOI: 10.1111/jsm.12177] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
INTRODUCTION Erectile dysfunction (ED) is a major health problem. We have shown that adrenomedullin (AM) restores erectile function in diabetic rats. AIM The aim of this study is to explore a better treatment for ED, we examined whether combination of AM and angiopoietin-1 (Ang-1) was more effective to treat ED than treatment with AM alone or Ang-1 alone. We also compared the effect of the combination therapy with that of treatment with vascular endothelial growth factor-A (VEGF-A). METHODS Male Wistar rats were injected with streptozotocin (STZ) to induce diabetes. Adenoviruses expressing AM (AdAM), Ang-1 (AdAng-1), and VEGF-A (AdVEGF-A) were injected into the penis 6 weeks after STZ administration. Erectile function, penile histology, and protein expression were analyzed 4 weeks after the injection of the adenoviruses. MAIN OUTCOME MEASURES Intracavernous pressure and mean arterial pressure were measured to evaluate erectile function. The morphology of the penis was analyzed by Elastica van Gieson stain and immunohistochemistry. The expression of α-smooth muscle actin (SMA), VE-cadherin and type I collagen was assessed by Western blot analysis. RESULTS Infection with AdAM plus AdAng-1 more effectively restored erectile function than infection with AdAM alone or AdAng-1 alone. This combination therapy restored erectile function to a level similar to that observed in the age-matched Wistar rats. Expression of SMA and VE-cadherin increased more significantly in the AdAM plus AdAng-1-treated group than in the AdAM- or AdAng-1-treated group. Although AdVEGF-A infection restored erectile function significantly, it also caused enlargement of the trabeculae of the cavernous body, aberrant angiogenesis, and overproduction of type I collagen. CONCLUSIONS These results suggested that combination therapy with AM and Ang-1 potently restored erectile function and normal morphology of the cavernous body compared with VEGF-A administration. This combination therapy will be useful to treat ED patients with a severely damaged cavernous body.
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Affiliation(s)
- Hiroaki Nishimatsu
- The Department of Urology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
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Molina F, Rus A, Peinado MA, del Moral ML. Short-term hypoxia/reoxygenation activates the angiogenic pathway in rat caudate putamen. J Biosci 2013; 38:363-71. [DOI: 10.1007/s12038-013-9327-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Iesato Y, Toriyama Y, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Yoshizawa T, Koyama T, Uetake R, Yang L, Yamauchi A, Tanaka M, Igarashi K, Murata T, Shindo T. Adrenomedullin-RAMP2 system is crucially involved in retinal angiogenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 182:2380-90. [PMID: 23562442 DOI: 10.1016/j.ajpath.2013.02.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2012] [Revised: 01/23/2013] [Accepted: 02/04/2013] [Indexed: 01/19/2023]
Abstract
Adrenomedullin (ADM) is an endogenous peptide first identified as a strong vasodilating molecule. We previously showed that in mice, homozygous knockout of ADM (ADM(-/-)) or its receptor regulating protein, RAMP2 (RAMP2(-/-)), is embryonically lethal due to abnormal vascular development, thereby demonstrating the importance of ADM and its receptor signaling to vascular development. ADM expression in the retina is strongly induced by ischemia; however, its role in retinal pathophysiology remains unknown. Here, we analyzed oxygen-induced retinopathy (OIR) using heterozygous ADM and RAMP2 knockout mice models (ADM(+/-) or RAMP2(+/-), respectively). In addition, we analyzed the role of the ADM-RAMP2 system during earlier stages of retinal angiogenesis using an inducible endothelial cell-specific RAMP2 knockout mouse line (DI-E-RAMP2(-/-)). Finally, we assessed the ability of antibody-induced ADM blockade to control pathological retinal angiogenesis in OIR. In OIR, neovascular tufts, avascular zones, and hypoxic areas were all smaller in ADM(+/-) retinas compared with wild-type mice. ADM(+/-) retinas also exhibited reduced levels of VEGF and eNOS expression. DI-E-RAMP2(-/-) showed abnormal retinal vascular patterns in the early stages of development. However, ADM enhanced the proliferation and migration of retinal endothelial cells. Finally, we found intravitreal injection of anti-ADM antibody reduced pathological retinal angiogenesis. In conclusion, the ADM-RAMP2 system is crucially involved in retinal angiogenesis. ADM and its receptor system are potential therapeutic targets for controlling pathological retinal angiogenesis.
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Affiliation(s)
- Yasuhiro Iesato
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
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Sakimoto S, Kidoya H, Kamei M, Naito H, Yamakawa D, Sakaguchi H, Wakabayashi T, Nishida K, Takakura N. An angiogenic role for adrenomedullin in choroidal neovascularization. PLoS One 2013; 8:e58096. [PMID: 23520487 PMCID: PMC3592925 DOI: 10.1371/journal.pone.0058096] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Accepted: 02/03/2013] [Indexed: 01/16/2023] Open
Abstract
Purpose Adrenomedullin (ADM) has been shown to take part in physiological and pathological angiogenesis. The purpose of this study was to investigate whether ADM signaling is involved in choroidal neovascularization (CNV) using a mouse model. Methods and Results CNV was induced by laser photocoagulation in 8-week-old C57BL/6 mice. ADM mRNA expression significantly increased following treatment, peaking 4 days thereafter. The expression of ADM receptor (ADM-R) components (CRLR, RAMP2 and RAMP 3) was higher in CD31+CD45− endothelial cells (ECs) than CD31−CD45− non-ECs. Inflammatory stimulation upregulated the expression of ADM not only in cell lines but also in cells in primary cultures of the choroid/retinal pigment epithelium complex. Supernatants from TNFα-treated macrophage cell lines potentiated the proliferation of ECs and this was partially suppressed by an ADM antagonist, ADM (22–52). Intravitreous injection of ADM (22–52) or ADM neutralizing monoclonal antibody (mAb) after laser treatment significantly reduced the size of CNV compared with vehicle-treated controls (p<0.01). Conclusions ADM signaling is involved in laser-induced CNV formation, because both an ADM antagonist and ADM mAb significantly inhibited it. Suppression of ADM signaling might be a valuable alternative treatment for CNV associated with age-related macular degeneration.
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Affiliation(s)
- Susumu Sakimoto
- Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Hiroyasu Kidoya
- Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
| | - Motohiro Kamei
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Hisamichi Naito
- Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
| | - Daishi Yamakawa
- Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
| | - Hirokazu Sakaguchi
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Taku Wakabayashi
- Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kohji Nishida
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Nobuyuki Takakura
- Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
- JST(Japan Science and Technology Agency), CREST, Tokyo, Japan
- * E-mail:
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Koyama T, Ochoa-Callejero L, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Iinuma N, Arai T, Yoshizawa T, Iesato Y, Lei Y, Uetake R, Okimura A, Yamauchi A, Tanaka M, Igarashi K, Toriyama Y, Kawate H, Adams RH, Kawakami H, Mochizuki N, Martínez A, Shindo T. Vascular endothelial adrenomedullin-RAMP2 system is essential for vascular integrity and organ homeostasis. Circulation 2013; 127:842-53. [PMID: 23355623 DOI: 10.1161/circulationaha.112.000756] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Revealing the mechanisms underlying the functional integrity of the vascular system could make available novel therapeutic approaches. We previously showed that knocking out the widely expressed peptide adrenomedullin (AM) or receptor activity-modifying protein 2 (RAMP2), an AM-receptor accessory protein, causes vascular abnormalities and is embryonically lethal. Our aim was to investigate the function of the vascular AM-RAMP2 system directly. METHODS AND RESULTS We generated endothelial cell-specific RAMP2 and AM knockout mice (E-RAMP2(-/-) and E-AM(-/-)). Most E-RAMP2(-/-) mice died perinatally. In surviving adults, vasculitis occurred spontaneously. With aging, E-RAMP2(-/-) mice showed severe organ fibrosis with marked oxidative stress and accelerated vascular senescence. Later, liver cirrhosis, cardiac fibrosis, and hydronephrosis developed. We next used a line of drug-inducible E-RAMP2(-/-) mice (DI-E-RAMP2(-/-)) to induce RAMP2 deletion in adults, which enabled us to analyze the initial causes of the aforementioned vascular and organ damage. Early after the induction, pronounced edema with enhanced vascular leakage occurred. In vitro analysis revealed the vascular leakage to be caused by actin disarrangement and detachment of endothelial cells. We found that the AM-RAMP2 system regulates the Rac1-GTP/RhoA-GTP ratio and cortical actin formation and that a defect in this system causes the disruption of actin formation, leading to vascular and organ damage at the chronic stage after the gene deletion. CONCLUSIONS Our findings show that the AM-RAMP2 system is a key determinant of vascular integrity and homeostasis from prenatal stages through adulthood. Furthermore, our models demonstrate how endothelial cells regulate vascular integrity and how their dysregulation leads to organ damage.
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Affiliation(s)
- Teruhide Koyama
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano, 390-8621, Japan
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Yuda K, Takahashi H, Inoue T, Ueta T, Iriyama A, Kadonosono K, Tamaki Y, Aburatani H, Nagai R, Yanagi Y. Adrenomedullin Inhibits Choroidal Neovascularization via CCL2 in the Retinal Pigment Epithelium. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 181:1464-72. [DOI: 10.1016/j.ajpath.2012.06.028] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Revised: 05/01/2012] [Accepted: 06/28/2012] [Indexed: 12/15/2022]
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Zhang W, Wang LJ, Xiao F, Wei Y, Ke W, Xin HB. Intermedin: a novel regulator for vascular remodeling and tumor vessel normalization by regulating vascular endothelial-cadherin and extracellular signal-regulated kinase. Arterioscler Thromb Vasc Biol 2012; 32:2721-32. [PMID: 22922959 DOI: 10.1161/atvbaha.112.300185] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVE Intermedin (IMD), a member of calcitonin family, was suggested to play a role in angiogenesis and cancer. The aim of this study was to investigate the role of IMD in the angiogenic process and the underlying mechanism, and the possibility for it to be used as a target for angiogenesis-based anticancer therapies. METHODS AND RESULTS Using in vivo and in vitro 3-dimensional angiogenic models, we found that IMD induced a well-ordered vasculature with hierarchical structure and had a synergistic effect with vascular endothelial growth factor. Using RNA interference, real-time polymerase chain reaction, and Western blot analysis, we found that IMD alleviated the undesirable effects of vascular endothelial growth factor by restricting the excessive vessel sprouting and uneven lumen formation through the regulation of vascular endothelial-cadherin and identified its receptor on the endothelial cells. Both mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphoinositide 3-kinase/Akt activation were involved in the effects. Furthermore, using experimental tumor models, we demonstrated that IMD was involved in tumor angiogenesis, and the blockade of IMD severely impaired blood supply and eventually inhibited tumor growth. CONCLUSIONS We demonstrated that IMD played a critical role in the vascular remodeling process and tumor angiogenesis and may serve as a novel target for the development of angiogenesis-based anticancer therapies.
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Affiliation(s)
- Wei Zhang
- Molecular Medicine Research Center, West China Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
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Belting M, Almgren P, Manjer J, Hedblad B, Struck J, Wang TJ, Bergmann A, Melander O. Vasoactive Peptides with Angiogenesis-Regulating Activity Predict Cancer Risk in Males. Cancer Epidemiol Biomarkers Prev 2012; 21:513-22. [DOI: 10.1158/1055-9965.epi-11-0840] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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