Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 14, 2025; 31(10): 100194
Published online Mar 14, 2025. doi: 10.3748/wjg.v31.i10.100194
Platelet activation relieves liver portal hypertension via the lymphatic system though the classical vascular endothelial growth factor receptor 3 signaling pathway
Min Chen, Jin-Bo Zhao, Guang-Bo Wu, Zheng-Hao Wu, Gu-Qing Luo, Zhi-Feng Zhao, Chi-Hao Zhang, Jia-Yun Lin, Hong-Jie Li, Xiao-Liang Qi, Hai-Zhong Huo, Abudukadier Tuersun, Qiang Fan, Lei Zheng, Meng Luo
Min Chen, Jin-Bo Zhao, Guang-Bo Wu, Zheng-Hao Wu, Gu-Qing Luo, Chi-Hao Zhang, Jia-Yun Lin, Hong-Jie Li, Xiao-Liang Qi, Hai-Zhong Huo, Abudukadier Tuersun, Qiang Fan, Lei Zheng, Meng Luo, Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
Min Chen, Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
Zhi-Feng Zhao, Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an 710032, Shaanxi Province, China
Co-first authors: Min Chen and Jin-Bo Zhao.
Co-corresponding authors: Lei Zheng and Meng Luo.
Author contributions: Chen M wrote the original draft; Zhao JB contributed to writing-reviewing and editing; Zhao ZF, Wu GB, Wu ZH, Luo GQ, and Zhang CH were responsible for data curation; Lin JY, Li HJ, Qi XL, Huo HZ, and Tuersun A account for methodology and supervision; Fan Q, Zheng L, and Luo M were in charge of supervision and funding acquisition; All authors read and approved of the final manuscript.
Supported by the National Natural Science Foundation of China, No. 82100639, No. 82200630, and No. 81970526; Postdoctoral Scientific Research Foundation of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No. 202401023; Clinical Research Program of Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No. JYLJ202124; Shanghai Municipal Commission of Health and Family Planning, No. 20244Y0195 and No. 20234Y0132; the Fundamental Research Program Funding of Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. JYZZ162; and Science Foundation of Xinjiang Uygur Natural Autonomous Region, No. 2022D01F17.
Institutional review board statement: This study does not involve any human experiments.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (IACUC protocol No. SH9H-2019-A201-1 and No. SH9H-2021-A233-SB).
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Meng Luo, MD, Chief Physician, Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, No. 639 Manufacturing Bureau Road, Shanghai 200011, China. luosh9hospital@sina.com
Received: August 9, 2024
Revised: December 16, 2024
Accepted: January 21, 2025
Published online: March 14, 2025
Processing time: 200 Days and 17.3 Hours
Abstract
BACKGROUND

Liver cirrhosis and portal hypertension (PHT) can lead to lymphatic abnormalities and coagulation dysfunction. Because lymphangiogenesis may relieve liver cirrhosis and PHT, the present study investigated the gene expression alterations in the lymphatic system and the effectiveness of platelet-mediated lymphangiogenesis in improving liver cirrhosis and PHT.

AIM

To investigate the role of lymphangiogenesis in preclinical PHT models.

METHODS

Immunohistochemistry and transcriptome sequencing of bile duct ligation (BDL) and control lymphatic samples were conducted to reveal the indicated signaling pathways. Functional enrichment analyses were performed on the differentially expressed genes and hub genes. Adenoviral infection of vascular endothelial growth factor C (VEGF-C), platelet-rich plasma (PRP), and VEGF3 receptor (VEGFR) inhibitor MAZ-51 was used as an intervention for the lymphatic system in PHT models. Histology, hemodynamic tests and western blot analyses were performed to demonstrate the effects of lymphatic intervention in PHT patients.

RESULTS

Lymphangiogenesis was increased in the BDL rat model. Transcriptome sequencing analysis of the extrahepatic lymphatic system revealed its close association with platelet adherence, aggregation, and activation. The role of PHT in the rat model was investigated by activating (PRP) and inhibiting (MAZ-51) the lymphatic system. PRP promoted lymphangiogenesis, which increased lymphatic drainage, alleviated portal pressure, reduced liver fibrosis, inhibited inflammation, inhibited angiogenesis, and suppressed mesenteric artery remodeling. MAZ-51 reversed the above improvements.

CONCLUSION

Via VEGF-C/VEGFR-3, platelets impede fibrosis, angiogenesis, and mesenteric artery remodeling, ultimately alleviating PHT. Thus, platelet intervention is a therapeutic approach for cirrhosis and PHT.

Keywords: Portal hypertension; Cirrhosis; Lymphangiogenesis; Platelets; Vascular endothelial growth factor C

Core Tip: In the sequencing of the classic bile duct ligation model of portal hypertension in rats, platelet activation plays a crucial role in lymphagiogenesis. Effective lymphatic drainage may alleviate the high flow fluid environment of the hepatic portal vein caused by various etiologies. Based on this research, platelet-rich plasma enhanced intrahepatic and extrahepatic proliferation of lymphatics and simultaneously alleviated portal hypertension.