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1
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Gomez Toledo A, Golden GJ, Cummings RD, Malmström J, Esko JD. Endothelial Glycocalyx Turnover in Vascular Health and Disease: Rethinking Endothelial Dysfunction. Annu Rev Biochem 2025; 94:561-586. [PMID: 40132227 DOI: 10.1146/annurev-biochem-032620-104745] [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: 03/27/2025]
Abstract
The endothelial glycocalyx, a glycan-rich layer on the luminal surface of endothelial cells lining blood and lymphatic vessels, plays a crucial role in vascular homeostasis by regulating vascular permeability, immune cell trafficking, and vascular tone. Dysregulated endothelial glycocalyx turnover-whether through altered synthesis, intracellular degradation, or shedding-contributes to endothelial dysfunction in conditions such as sepsis, ischemic events, and chronic inflammatory disorders including diabetes and atherosclerosis. In this review, we examine the structure, function, and turnover of the endothelial glycocalyx, emphasizing how pathological changes in its turnover drive vascular dysfunction. We also highlight diagnostic approaches to evaluate dysregulated endothelial glycocalyx turnover in connection with vascular diseases and discuss therapeutic strategies aimed at preventing endothelial glycocalyx degradation and restoring endothelial function.
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Affiliation(s)
| | - Gregory J Golden
- Department of Cellular and Molecular Medicine and Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California, USA;
| | - Richard D Cummings
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Johan Malmström
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Jeffrey D Esko
- Department of Cellular and Molecular Medicine and Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California, USA;
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2
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He K, Ren H, Chen X, He F, Zhang Y, Zhang H, Li F, Yu S. Shed Syndecan-4 and Its Possible Roles in Osteoarthritis. Biomedicines 2025; 13:1037. [PMID: 40426865 PMCID: PMC12109450 DOI: 10.3390/biomedicines13051037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 04/15/2025] [Accepted: 04/22/2025] [Indexed: 05/29/2025] Open
Abstract
The specific pathogenesis of osteoarthritis (OA) remains not fully understood. As a transmembrane heparan sulfate proteoglycan, syndecan-4 (SDC4) has been proven to play an important role in the development of OA. Notably, the extracellular domain of SDC4 can be cleaved by proteolytic enzymes, leading to the release of shed SDC4 (sSDC4), which subsequently regulates various biological processes in an autocrine or paracrine manner. This review analyzed 97 publications (1987-2025) from Pubmed and the Web of Science Core Collection using specific key words (syndecan-4, shed syndecan-4, and osteoarthritis), providing a comprehensive overview of the current research on sSDC4, including its shedding enzymes and specific cleavage sites, as well as the factors and mechanisms that influence SDC4 shedding. Furthermore, it summarizes the functions of both sSDC4 and its remaining membrane-bound domain. Finally, the roles of sSDC4 in OA are discussed to identify potential therapeutic targets and explore new strategies for the treatment of OA.
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Affiliation(s)
- Kangping He
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, School of Stomatology, The Fourth Military Medical University, Xi’an 710032, China
| | - Haozhe Ren
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, School of Stomatology, The Fourth Military Medical University, Xi’an 710032, China
- School/Hospital of Stomatology, Lanzhou University, Lanzhou 730000, China
| | - Xiaohua Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, School of Stomatology, The Fourth Military Medical University, Xi’an 710032, China
| | - Feng He
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, School of Stomatology, The Fourth Military Medical University, Xi’an 710032, China
| | - Yueying Zhang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Department of Orthodontics, College of Stomatology, Xi’an Jiaotong University, Xi’an 710049, China
| | - Hongyun Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, School of Stomatology, The Fourth Military Medical University, Xi’an 710032, China
| | - Feifei Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, School of Stomatology, The Fourth Military Medical University, Xi’an 710032, China
| | - Shibin Yu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, School of Stomatology, The Fourth Military Medical University, Xi’an 710032, China
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3
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Çakir MU, Karduz G, Aksu U. Experimental and clinical perspectives on glycocalyx integrity and its relation to acute respiratory distress syndrome. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167745. [PMID: 39987847 DOI: 10.1016/j.bbadis.2025.167745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 02/02/2025] [Accepted: 02/18/2025] [Indexed: 02/25/2025]
Abstract
The development of microcirculation imaging devices has significantly advanced our comprehension of the capillary environment's dynamics. Early research suggested that erythrocytes did not contact the vessel's inner surface due to the Fåhraeus effect, implying the presence of a covering on the endothelial cell surface. Subsequent electron microscopy studies revealed this layer to be a complex part of the vessel wall, now known as the endothelial glycocalyx (EG). The EG is a network of proteoglycans and glycoproteins bound to the endothelial membrane, incorporating soluble molecules from the endothelium and plasma. Over time, studies have elucidated the structure, function, and therapeutic targets of the glycocalyx, underscoring its pivotal role in vascular biology. The presence of cellular extensions of lung tissue cells in both vascular and nonvascular areas demonstrates the pivotal role of the glycocalyx in pulmonary vascular leak, surfactant dysfunction, impaired lung compliance and gas exchange abnormalities, which are hallmarks of acute respiratory distress syndrome (ARDS). It is of the utmost importance to elucidate the mechanisms underlying alveolocapillary glycocalyx degradation to develop efficacious treatments for ARDS, which has a mortality rate of 35 %. An understanding of the glycocalyx's role in vascular integrity provides a foundation for exploring new therapeutic avenues to mitigate lung injury and improve clinical outcomes in ARDS patients.
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Affiliation(s)
- Muzaffer Utku Çakir
- Department of Biology, Faculty of Science, Istanbul University, Istanbul, Türkiye
| | - Gülsüm Karduz
- Department of Biology, Faculty of Science, Istanbul University, Istanbul, Türkiye
| | - Ugur Aksu
- Department of Biology, Faculty of Science, Istanbul University, Istanbul, Türkiye.
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4
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Bartkowiak K, Bartkowiak M, Jankowska-Steifer E, Ratajska A, Czarnowska E, Kujawa M, Aniołek O, Niderla-Bielińska J. Expression of mRNA for molecules that regulate angiogenesis, endothelial cell survival, and vascular permeability is altered in endothelial cells isolated from db/db mouse hearts. Histochem Cell Biol 2024; 162:523-539. [PMID: 39317805 PMCID: PMC11455669 DOI: 10.1007/s00418-024-02327-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/16/2024] [Indexed: 09/26/2024]
Abstract
Metabolic syndrome (MetS) is a condition that includes symptoms, such as obesity, hyperglycemia, and hypertension, which elevate cardiovascular risk. An impaired angiogenic response of endothelial cells (ECs) in heart and peripheral organs has been proposed in MetS, but the mechanisms of this phenomenon have not been thoroughly explored. Results obtained from evaluating the whole myocardium are inconsistent, since different types of cells react differently to MetS environment and a variety of molecular pathways are involved in the angiogenic response. Therefore, the aim of this paper was to study one selected pathway-the VEGF/VEGFR pathway, which regulates the angiogenic response and microvascular permeability in ECs isolated from db/db mouse hearts. The expression of mRNAs for VEGF/VEGFR axis proteins was assessed with RT-PCR in ECs isolated from control and db/db mouse myocardium. The density of CD31-, VEGFR2-, and VE-cadherin-positive cells was examined with confocal microscopy, and the ultrastructure of ECs was analyzed with transmission electron microscopy. The aortic ring assay was used to assess the capacity of ECs to respond to angiogenic stimuli. Our results showed a decreased number of microvessels, diminished expression of VE-cadherin and VEGFR2 and widened gaps between the ECs of microcapillaries. The aortic ring assay showed a diminished number of sprouts in db/db mice. These results may indicate that ECs in MetS enhance the production of mRNA for VEGF/VRGFR axis proteins, yet sprout formation and vascular barrier maintenance are limited. These novel data may provide a foundation for further studies on ECs dysfunction in MetS.
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Affiliation(s)
- Krzysztof Bartkowiak
- Histology and Embryology Department, Medical University of Warsaw, Chalubinskiego 5 Str, 02-004, Warsaw, Poland
| | - Mateusz Bartkowiak
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Ewa Jankowska-Steifer
- Histology and Embryology Department, Medical University of Warsaw, Chalubinskiego 5 Str, 02-004, Warsaw, Poland
| | - Anna Ratajska
- Department of Pathology, Medical University of Warsaw, Warsaw, Poland
| | | | - Marek Kujawa
- Department of Histology and Embryology, Faculty of Medicine, Lazarski University, Warsaw, Poland
| | - Olga Aniołek
- Department of Histology and Embryology, Faculty of Medicine, Lazarski University, Warsaw, Poland
| | - Justyna Niderla-Bielińska
- Histology and Embryology Department, Medical University of Warsaw, Chalubinskiego 5 Str, 02-004, Warsaw, Poland.
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5
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Rajabloo Y, Saberi-Karimian M, Soflaei SS, Ferns GA, Ghayour-Mobarhan M. Syndecans and diabetic complications: A narrative review. Am J Med Sci 2024; 368:99-111. [PMID: 38697476 DOI: 10.1016/j.amjms.2024.04.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 04/20/2024] [Accepted: 04/26/2024] [Indexed: 05/05/2024]
Abstract
Syndecan (SDC) is a member of the heparan sulfate proteoglycan (HSPG) family. It appears to play a role in the aetiology of diabetic complications, with decreased levels of SDCs being reported in the kidney, retina, and cardiac muscle in models of diabetes mellitus (DM). The reduced levels of SDCs may play an important role in the development of albuminuria in DM. Some studies have provided the evidence supporting the mechanisms underlying the role of SDCs in DM. However, SDCs and the molecular mechanisms involved are complex and need to be further elucidated. This review focuses on the underlying molecular mechanisms of SDCs that are involved in the development and progression of the complications of DM, which may help in developing new strategies to prevent and treat these complications.
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Affiliation(s)
- Yasamin Rajabloo
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Saberi-Karimian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran; Endoscopic and Minimally Invasive Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Sara Saffar Soflaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK
| | - Majid Ghayour-Mobarhan
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
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6
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Kunnathattil M, Rahul P, Skaria T. Soluble vascular endothelial glycocalyx proteoglycans as potential therapeutic targets in inflammatory diseases. Immunol Cell Biol 2024; 102:97-116. [PMID: 37982607 DOI: 10.1111/imcb.12712] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 10/30/2023] [Accepted: 10/30/2023] [Indexed: 11/21/2023]
Abstract
Reducing the activity of cytokines and leukocyte extravasation is an emerging therapeutic strategy to limit tissue-damaging inflammatory responses and restore immune homeostasis in inflammatory diseases. Proteoglycans embedded in the vascular endothelial glycocalyx, which regulate the activity of cytokines to restrict the inflammatory response in physiological conditions, are proteolytically cleaved in inflammatory diseases. Here we critically review the potential of proteolytically shed, soluble vascular endothelial glycocalyx proteoglycans to modulate pathological inflammatory responses. Soluble forms of the proteoglycans syndecan-1, syndecan-3 and biglycan exert beneficial anti-inflammatory effects by the removal of chemokines, suppression of proinflammatory cytokine expression and leukocyte migration, and induction of autophagy of proinflammatory M1 macrophages. By contrast, soluble versikine and decorin enhance proinflammatory responses by increasing inflammatory cytokine synthesis and leukocyte migration. Endogenous syndecan-2 and mimecan exert proinflammatory effects, syndecan-4 and perlecan mediate beneficial anti-inflammatory effects and glypican regulates Hh and Wnt signaling pathways involved in systemic inflammatory responses. Taken together, targeting the vascular endothelial glycocalyx-derived, soluble syndecan-1, syndecan-2, syndecan-3, syndecan-4, biglycan, versikine, mimecan, perlecan, glypican and decorin might be a potential therapeutic strategy to suppress overstimulated cytokine and leukocyte responses in inflammatory diseases.
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Affiliation(s)
- Maneesha Kunnathattil
- Department of Zoology, Government College Madappally, University of Calicut, Calicut, Kerala, India
| | - Pedapudi Rahul
- School of Biotechnology, National Institute of Technology Calicut, Calicut, Kerala, India
| | - Tom Skaria
- School of Biotechnology, National Institute of Technology Calicut, Calicut, Kerala, India
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7
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Schalkwijk CG, Micali LR, Wouters K. Advanced glycation endproducts in diabetes-related macrovascular complications: focus on methylglyoxal. Trends Endocrinol Metab 2023; 34:49-60. [PMID: 36446668 DOI: 10.1016/j.tem.2022.11.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 11/11/2022] [Accepted: 11/11/2022] [Indexed: 11/29/2022]
Abstract
Diabetes is associated with vascular injury and the onset of macrovascular complications. Advanced glycation endproducts (AGEs) and the AGE precursor methylglyoxal (MGO) have been identified as key players in establishing the relationship between diabetes and vascular injury. While most research has focused on the link between AGEs and vascular injury, less is known about the effects of MGO on vasculature. In this review, we focus on the mechanisms linking AGEs and MGO to the development of atherosclerosis. AGEs and MGO are involved in many stages of atherosclerosis progression. However, more research is needed to determine the exact mechanisms underlying these effects. Nevertheless, AGEs and MGO could represent valid therapeutic targets for the macrovascular complications of diabetes.
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Affiliation(s)
- Casper G Schalkwijk
- Department of Internal Medicine, CARIM School for Cardiovascular Diseases, MUMC+, Maastricht, The Netherlands
| | | | - Kristiaan Wouters
- Department of Internal Medicine, CARIM School for Cardiovascular Diseases, MUMC+, Maastricht, The Netherlands.
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Milusev A, Rieben R, Sorvillo N. The Endothelial Glycocalyx: A Possible Therapeutic Target in Cardiovascular Disorders. Front Cardiovasc Med 2022; 9:897087. [PMID: 35647072 PMCID: PMC9136230 DOI: 10.3389/fcvm.2022.897087] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 04/21/2022] [Indexed: 12/15/2022] Open
Abstract
The physiological, anti-inflammatory, and anti-coagulant properties of endothelial cells (ECs) rely on a complex carbohydrate-rich layer covering the luminal surface of ECs, called the glycocalyx. In a range of cardiovascular disorders, glycocalyx shedding causes endothelial dysfunction and inflammation, underscoring the importance of glycocalyx preservation to avoid disease initiation and progression. In this review we discuss the physiological functions of the glycocalyx with particular focus on how loss of endothelial glycocalyx integrity is linked to cardiovascular risk factors, like hypertension, aging, diabetes and obesity, and contributes to the development of thrombo-inflammatory conditions. Finally, we consider the role of glycocalyx components in regulating inflammatory responses and discuss possible therapeutic interventions aiming at preserving or restoring the endothelial glycocalyx and therefore protecting against cardiovascular disease.
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Affiliation(s)
- Anastasia Milusev
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences (GCB), University of Bern, Bern, Switzerland
| | - Robert Rieben
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Nicoletta Sorvillo
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- *Correspondence: Nicoletta Sorvillo
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9
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Belvedere R, Morretta E, Pessolano E, Novizio N, Tosco A, Porta A, Whiteford J, Perretti M, Filippelli A, Monti MC, Petrella A. Mesoglycan exerts its fibrinolytic effect through the activation of annexin A2. J Cell Physiol 2021; 236:4926-4943. [PMID: 33284486 DOI: 10.1002/jcp.30207] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 11/20/2020] [Accepted: 11/24/2020] [Indexed: 12/12/2022]
Abstract
Mesoglycan is a drug based on a mixture of glycosaminoglycans mainly used for the treatment of blood vessel diseases acting as antithrombotic and profibrinolytic drugs. Besides the numerous clinical studies, there is no information about its function on the fibrinolytic cascade. Here, we have elucidated the mechanism of action by which mesoglycan induces the activation of plasmin from endothelial cells. Surprisingly, by a proteomic analysis, we found that, following mesoglycan treatment, these cells show a notable amount of annexin A2 (ANXA2) at the plasma membrane. This protein has been widely associated with fibrinolysis and appears able to move to the membrane when phosphorylated. In our model, this translocation has proven to enhance cell migration, invasion, and angiogenesis. Furthermore, the interaction of mesoglycan with syndecan 4 (SDC4), a coreceptor belonging to the class of heparan sulfate proteoglycans, represents the upstream event of the ANXA2 behavior. Indeed, the activation of SDC4 triggers the motility of endothelial cells culminating in angiogenesis. Interestingly, mesoglycan can induce the release of plasmin in endothelial cell supernatants only in the presence of ANXA2. This evaluation suggests that mesoglycan triggers the formation of a chain mechanism starting from the activation of SDC4, and the related cascade of events, including src complex and PKCα activation, promoting the phosphorylation of ANXA2 and its translocation to plasma membrane. This indicates a connection among mesoglycan, SDC4-(PKCα-src), and ANXA2 which, in turn, links the tissue plasminogen activator bringing it closer to plasminogen. This latter is so cleaved to release the plasmin and degrade fibrin sleeves.
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Affiliation(s)
| | - Elva Morretta
- Department of Pharmacy, University of Salerno, Fisciano (SA), Italy
| | - Emanuela Pessolano
- Department of Pharmacy, University of Salerno, Fisciano (SA), Italy
- The William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Nunzia Novizio
- Department of Pharmacy, University of Salerno, Fisciano (SA), Italy
| | - Alessandra Tosco
- Department of Pharmacy, University of Salerno, Fisciano (SA), Italy
| | - Amalia Porta
- Department of Pharmacy, University of Salerno, Fisciano (SA), Italy
| | - James Whiteford
- The William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Mauro Perretti
- The William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Amelia Filippelli
- Department of Medicine, Surgery, and Dentistry, University of Salerno, Baronissi (SA), Italy
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Syndecans in cancer: A review of function, expression, prognostic value, and therapeutic significance. Cancer Treat Res Commun 2021; 27:100312. [PMID: 33485180 DOI: 10.1016/j.ctarc.2021.100312] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/10/2021] [Accepted: 01/11/2021] [Indexed: 12/11/2022]
Abstract
While our understanding of tumors and how to treat them has advanced significantly since the days of Aminopterin and the radical mastectomy, cancer remains among the leading causes of death worldwide. Despite innumerable advancements in medical technology the non-static and highly heterogeneous nature of a tumor can make characterization and treatment exceedingly difficult. Because of this complexity, the identification of new cellular constituents that can be used for diagnostic, prognostic, and therapeutic purposes is crucial in improving patient outcomes worldwide. Growing evidence has demonstrated that among the myriad of changes seen in cancer cells, the Syndecan family of proteins has been observed to undergo drastic alterations in expression. Syndecans are transmembrane heparan sulfate proteoglycans that are responsible for cell signaling, proliferation, and adhesion, and many studies have shed light on their unique involvement in both tumor progression and suppression. This review seeks to discuss Syndecan expression levels in various cancers, whether they make reliable biomarkers for detection and prognosis, and whether they may be viable targets for future cancer therapies. The conclusions drawn from the literature reviewed in this article indicate that changes in expression of Syndecan protein can have profound effects on tumor size, metastatic capability, and overall patient survival rate. Further, while data regarding the therapeutic targeting of Syndecan proteins is sparse, the available literature does demonstrate promise for their use in cancer treatment going forward.
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Jaiswal AK, Sadasivam M, Aja S, Hamad ARA. Lack of Syndecan-1 produces significant alterations in whole-body composition, metabolism and glucose homeostasis in mice. World J Diabetes 2020; 11:126-136. [PMID: 32313611 PMCID: PMC7156300 DOI: 10.4239/wjd.v11.i4.126] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/18/2020] [Accepted: 02/11/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Obesity is a disease state with serious adverse metabolic complications, including glucose intolerance and type 2 diabetes that currently has no cure. Identifying and understanding roles of various modulators of body composition and glucose homeostasis is required for developing effective cures. Syndecan-1 (Sdc1) is a member of the heparan sulfate proteoglycan family that has mainly been investigated for its role in regulating proliferation and survival of epithelia and tumor cells, but little is known about its roles in regulating obesity and glucose homeostasis.
AIM To examine the role of Sdc1 in regulating body fat and glucose metabolism.
METHODS We used female wild type and Sdc1 knockout (Sdc1 KO) mice on BALB/c background and multiple methods. Metabolic measurements (rates of oxygen consumption, carbon dioxide production, respiratory exchange ratio and energy expenditure) were performed using an open-flow indirect calorimeter with additional features to measure food intake and physical activity. Glucose intolerance and insulin resistance were measured by established tolerance test methods.
RESULTS Although our primary goal was to investigate the effects of Sdc1 deficiency on body fat and glucose homeostasis, we uncovered that Sdc1 regulates multiple metabolic parameters. Sdc1KO mice have reduced body weight due to significant decreases in fat and lean masses under both chow and high fat diet conditions. The reduced body weight was not due to changes in food intakes, but Sdc1 KO mice exhibited altered feeding behavior as they ate more during the dark phase and less during the light phase than wild type mice. In addition, Sdc1 KO mice suffered from high rate of energy expenditure, glucose intolerance and insulin resistance.
CONCLUSION These results reveal critical multisystem and opposing roles for Sdc1 in regulating normal energy balance and glucose homeostasis. The results will have important implications for targeting Sdc1 to modulate metabolic parameters. Finally, we offer a novel hypothesis that could reconcile the opposing roles associated with Sdc1 deficiency.
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Affiliation(s)
- Anil Kumar Jaiswal
- Department of Pathobiology, Johns Hopkins University, Baltimore, MD 21205, United States
| | - Mohanraj Sadasivam
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, United States
| | - Susan Aja
- Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, United States
| | - Abdel Rahim A Hamad
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, United States
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12
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Abstract
Syndecans are transmembrane proteoglycans with heparan and chondroitin sulfate chains attached to their extracellular domain. Like many proteoglycans, they interact with a large number of ligands, such as growth factors, adhesion receptors, soluble small molecules, proteinases, and other extracellular matrix proteins to initiate downstream signaling pathways. Syndecans play a major role in inflammation, mainly by regulating leukocyte extravasation and cytokine function. At the same time, syndecans can undergo cytokine mediated changes in their expression levels during inflammation. The function of syndecans during inflammation appears to depend on the stage of inflammation, sulfation of heparan/chondroitin sulfate chains, the rate of ectodomain shedding and the solubility of the ectodomains. From the current literature, it is clear that syndecans are not only involved in the initial recruitment of pro-inflammatory molecules but also in establishing a balanced progression of inflammation. This review will summarize how cell surface and soluble syndecans regulate multiple aspects of inflammation.
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Affiliation(s)
- Sandeep Gopal
- Development and Stem Cells Program, Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
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13
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Jannaway M, Yang X, Meegan JE, Coleman DC, Yuan SY. Thrombin-cleaved syndecan-3/-4 ectodomain fragments mediate endothelial barrier dysfunction. PLoS One 2019; 14:e0214737. [PMID: 31091226 PMCID: PMC6519803 DOI: 10.1371/journal.pone.0214737] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 03/19/2019] [Indexed: 01/25/2023] Open
Abstract
Objective The endothelial glycocalyx constitutes part of the endothelial barrier but its degradation leaves endothelial cells exposed to transmigrating cells and circulating mediators that can damage the barrier or promote intercellular gaps. Syndecan proteins are key components of the endothelial glycocalyx and are shed during disease states where expression and activity of proteases such as thrombin are elevated. We tested the ability of thrombin to cleave the ectodomains of syndecans and whether the products could act directly on endothelial cells to alter barrier function. Approach and results Using transmission electron microscopy, we illustrated the presence of glycocalyx in human lung microvasculature. We confirmed expression of all syndecan subtypes on the endothelial surface of agarose-inflated human lungs. ELISA and western blot analysis suggested that thrombin can cleave syndecan-3/-4 ectodomains to produce fragments. In vivo, syndecan-3 ectodomain fragments increased extravasation of albumin-bound Evans blue in mouse lung, indicative of plasma protein leakage into the surrounding tissue. Syndecan-3/-4 ectodomain fragments decreased transendothelial electrical resistance, a measure of cell-cell adhesive barrier integrity, in a manner sensitive to a Rho kinase inhibitor. These effects were independent of glycosylation and thrombin receptor PAR1. Moreover, these cleavage products caused rapid VE-cadherin-based adherens junction disorganization and increased F-actin stress fibers, supporting their direct effect on endothelial paracellular permeability. Conclusions We suggest that thrombin can cleave syndecan-3/4 ectodomain into fragments which interact with endothelial cells causing paracellular hyperpermeability. This may have important implications in the pathogenesis of vascular dysfunction during sepsis or thrombotic disease states where thrombin is activated.
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Affiliation(s)
- Melanie Jannaway
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America
| | - Xiaoyuan Yang
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America
| | - Jamie E. Meegan
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America
| | - Danielle C. Coleman
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America
| | - Sarah Y. Yuan
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America
- * E-mail:
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14
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Li S, Zhang T, Zhou X, Du Z, Chen F, Luo J, Liu Q. The tumor suppressor role of miR-155-5p in gastric cancer. Oncol Lett 2018; 16:2709-2714. [PMID: 30008945 DOI: 10.3892/ol.2018.8932] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 04/24/2018] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is the fifth most common type of malignant tumor worldwide and the most common cause of cancer-associated mortality in China. Recent studies revealed that microRNAs (miRNAs) function in the pathogenesis of GC, and that miR-155-5p expression is downregulated in GC tissues. However, the function of miR-155-5p has not been fully identified. In the present study, it was demonstrated that overexpression of miR-155-5p inhibited GC-cell proliferation and promoted apoptosis, while downregulation of miR-155-5p promoted GC-cell proliferation and decreased the cisplatin sensitivity of GC cells. Mitogen-activated protein kinase kinase kinase 10 was demonstrated to be a potential target gene of miR-155-5p. In conclusion, an antitumor role of miR-155-5p in gastric cancer was suggested.
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Affiliation(s)
- Shiqing Li
- Department of Gastroenterology, Center Hospital of Nanchong City, The Second Clinical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Tao Zhang
- Department of Gastroenterology, Center Hospital of Nanchong City, The Second Clinical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Xiaoqing Zhou
- Department of Gastroenterology, Center Hospital of Nanchong City, The Second Clinical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Zonghan Du
- Department of Gastroenterology, Center Hospital of Nanchong City, The Second Clinical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Fumin Chen
- Department of Gastroenterology, Center Hospital of Nanchong City, The Second Clinical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Jun Luo
- Department of Gastroenterology, Center Hospital of Nanchong City, The Second Clinical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Qingsong Liu
- Clinical Laboratory Department, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
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15
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Resveratrol Improves Tube Formation in AGE-Induced Late Endothelial Progenitor Cells by Suppressing Syndecan-4 Shedding. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:9045976. [PMID: 29849922 PMCID: PMC5914122 DOI: 10.1155/2018/9045976] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 02/25/2018] [Indexed: 02/07/2023]
Abstract
Dysfunction of endothelial progenitor cells (EPCs) contributes to cardiovascular complications in diabetes, and resveratrol has been shown to improve EPC functions. Syndecan-4 (Synd4), a cell surface heparin sulfate proteoglycan, has been shown to promote neovascularization. Thus, the present study was performed to determine whether resveratrol promoted angiogenesis of EPCs by regulating Synd4. Late EPCs were isolated from human peripheral blood and stimulated with AGEs. Western blot showed that AGEs induced Synd4 shedding in a dose- and time-dependent manner. AGE-induced Synd4 shedding was partly reversed by NAC or resveratrol, along with normalized ROS production. Overexpression of Synd4 or pretreatment of resveratrol reversed AGE-impaired tube formation of EPCs and regulated the Akt/eNOS pathway. Furthermore, resveratrol suppressed Synd4 shedding via the inhibition of oxidative stress and improved tube formation of late EPCs via the regulation of the Synd4/Akt/eNOS pathway.
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16
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Yu X, Ma C, Fu L, Dong J, Ying J. MicroRNA-139 inhibits the proliferation, migration and invasion of gastric cancer cells by directly targeting ρ-associated protein kinase 1. Oncol Lett 2018; 15:5977-5982. [PMID: 29552227 DOI: 10.3892/ol.2018.8038] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 10/24/2017] [Indexed: 12/18/2022] Open
Abstract
The expression, function and underlying mechanisms of microRNA-139 (miR-139) in gastric cancer were investigated in the present study. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to detect miR-139 expression in gastric cancer tissues and cell lines. The effects of miR-139 overexpression on gastric cancer cell proliferation, migration and invasion were evaluated. ρ-associated protein kinase 1 (ROCK1) was predicted as a downstream target of miR-139 and its role in gastric cancer was assessed by bioinformatics analysis, luciferase reporter assay, RT-qPCR and western blot analysis. ROCK1 overexpression was established to investigate if the effects of miR-139 on gastric cancer cells may be attenuated. The results indicated that miR-139 was aberrantly downregulated in gastric cancer tissues and cell lines. Increased miR-139 expression reduced gastric cancer cell proliferation, migration and invasion. ROCK1 was demonstrated to be a direct target of miR-139 in gastric cancer and ROCK1 overexpression reversed the suppressive effects on gastric cancer cell proliferation, migration and invasion induced by miR-139 overexpression. The present study provides clear evidence demonstrating the anti-oncogenic activity of miR-139 in human gastric cancer, as mediated by the targeted downregulation of ROCK1.
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Affiliation(s)
- Xuechun Yu
- Department of Gastroenterology, People's Hospital of Xuyi, Huai'an, Jiangsu 211700, P.R. China
| | - Chaojian Ma
- Department of Gastroenterology, People's Hospital of Xuyi, Huai'an, Jiangsu 211700, P.R. China
| | - Ling Fu
- Department of Gastroenterology, People's Hospital of Xuyi, Huai'an, Jiangsu 211700, P.R. China
| | - Jingwu Dong
- Department of Gastroenterology, People's Hospital of Xuyi, Huai'an, Jiangsu 211700, P.R. China
| | - Jie Ying
- Department of Infectious Diseases, People's Hospital of Xuyi, Huai'an, Jiangsu 211700, P.R. China
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17
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Extracellular Matrix, a Hard Player in Angiogenesis. Int J Mol Sci 2016; 17:ijms17111822. [PMID: 27809279 PMCID: PMC5133823 DOI: 10.3390/ijms17111822] [Citation(s) in RCA: 157] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 09/30/2016] [Accepted: 10/21/2016] [Indexed: 12/11/2022] Open
Abstract
The extracellular matrix (ECM) is a complex network of proteins, glycoproteins, proteoglycans, and polysaccharides. Through multiple interactions with each other and the cell surface receptors, not only the ECM determines the physical and mechanical properties of the tissues, but also profoundly influences cell behavior and many physiological and pathological processes. One of the functions that have been extensively explored is its impingement on angiogenesis. The strong impact of the ECM in this context is both direct and indirect by virtue of its ability to interact and/or store several growth factors and cytokines. The aim of this review is to provide some examples of the complex molecular mechanisms that are elicited by these molecules in promoting or weakening the angiogenic processes. The scenario is intricate, since matrix remodeling often generates fragments displaying opposite effects compared to those exerted by the whole molecules. Thus, the balance will tilt towards angiogenesis or angiostasis depending on the relative expression of pro- or anti-angiogenetic molecules/fragments composing the matrix of a given tissue. One of the vital aspects of this field of research is that, for its endogenous nature, the ECM can be viewed as a reservoir to draw from for the development of new more efficacious therapies to treat angiogenesis-dependent pathologies.
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18
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Nakao M, Sugaya M, Takahashi N, Otobe S, Nakajima R, Oka T, Kabasawa M, Suga H, Morimura S, Miyagaki T, Fujita H, Asano Y, Sato S. Increased syndecan-4 expression in sera and skin of patients with atopic dermatitis. Arch Dermatol Res 2016; 308:655-660. [PMID: 27591995 DOI: 10.1007/s00403-016-1683-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 08/08/2016] [Accepted: 08/31/2016] [Indexed: 01/19/2023]
Abstract
Syndecan-4 (SDC-4) is a cell surface proteoglycan, which participates in signaling during cell adhesion, migration, proliferation, endocytosis, and mechanotransduction, and is expressed on various cells, including endothelial cells, epithelial cells, T cells, and eosinophils. Emerging evidences have suggested that SDC-4 might contribute to Th2-driven allergic immune responses. Here, we examined the role of SDC-4 in patients with atopic dermatitis (AD). Serum SDC-4 levels in AD patients were significantly higher than in healthy individuals, and they increased according to the disease severity. Importantly, they positively correlated with Eczema Area and Severity Index and itch visual analogue scale scores. Furthermore, serum SDC-4 levels decreased after treatment. We also analyzed SDC-4 expression in AD lesional skin. SDC-4 mRNA levels in AD skin were significantly higher than those of normal skin. Immunohistochemical staining revealed that SDC-4 was highly expressed in the epidermis and endothelial cells in AD lesional skin. Taken together, our study has demonstrated that SDC-4 expression was increased in sera and skin of AD patients, suggesting that SDC-4 may contribute to the development of AD.
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Affiliation(s)
- Momoko Nakao
- Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Makoto Sugaya
- Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Naomi Takahashi
- Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Sayaka Otobe
- Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Rina Nakajima
- Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Tomonori Oka
- Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Miyoko Kabasawa
- Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Hiraku Suga
- Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Sohshi Morimura
- Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Tomomitsu Miyagaki
- Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Hideki Fujita
- Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Yoshihide Asano
- Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Shinichi Sato
- Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
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