lancet-header
Preprints with The Lancet is part of SSRN´s First Look, a place where journals and other research experts identify content of interest prior to publication. These preprint papers are not peer-reviewed and are posted here as part of a 12-month trial. Authors have either opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet, or submitted directly via SSRN. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. These papers should not be used for clinical decision making or reporting of research to a lay audience without indicating that this is preliminary research that has not been peer-reviewed. For more information see the Comment published in The Lancet, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com

Neuropilin-1 Aggravates Liver Cirrhosis by Promoting Angiogenesis Via VEGFR2-Dependent PI3K/Akt Pathway in Hepatic Sinusoidal Endothelial Cells

34 Pages Posted: 11 Mar 2019

See all articles by Le Wang

Le Wang

Shandong University - Department of Gastroenterology

Yuemin Feng

Shandong University - Department of Gastroenterology

Xiaoyu Xie

Shandong University - Department of Gastroenterology

Hao Wu

Shandong University - Department of Gastroenterology

Xiao nan Su

Shandong University - Department of Gastroenterology

Jianni Qi

Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control

Wei Xin

Shandong University - Shandong Provincial Hospital

Lifen Gao

Shandong University

Ying Zhang

Johns Hopkins University - Department of Molecular Microbiology and Immunology

Vijay H. Shah

Mayo Clinic and Mayo Foundation

Qiang Zhu

Shandong University - Department of Gastroenterology; Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control

More...

Abstract

Liver fibrosis is a common liver injury characterized by excessive extracellular matrix deposition and increased intrahepatic angiogenesis. We have revealed that neuropilin-1(NRP-1) promoted hepatic stellate cell activation and liver fibrosis through its profibrogenic signaling pathways, PDGF/TGF-β. However, the role of NRP-1 in intrahepatic angiogenesis in hepatic sinusoidal endothelial cells (HSECs) during liver cirrhosis remains unclear. In this study, higher expression of NRP-1 in HSECs was detected in both human and murine cirrhotic liver tissues by immunohistochemical staining, quantitative real-time PCR and western blot assays. Interestingly, we found that the expression of NRP-1 was positively correlated with the expression of VEGFR2 and CD31 in liver cirrhosis. In vitro, the role of NRP-1 in regulating VEGFR2-dependent intrahepatic angiogenesis was identified in endothelial cells (ECs). NRP-1 knockdown suppressed the expression and activation of VEGFR2, accompanied by reduced ability of angiogenesis and migration of ECs. On the contrary, NRP-1 over-expression in ECs upregulated VEGFR2 expression and activation, promoted tube formation and migration of ECs. Mechanistically, NRP-1 modulated the expression of VEGFR2 by regulating FAK and its kinase activity. Furthermore, NRP-1 promoted VEGFR2-dependent angiogenesis via PI3K/Akt pathway in HSECs. Blocking NRP-1 function suppressed neoangiogenesis in HSECs, and reduced intrahepatic angiogenesis and fibrosis associated factors in vitro liver histoculture. In conclusion, NRP-1 promotes intrahepatic angiogenesis by upregulating the expression and activation of VEGFR2 through PI3K/Akt signaling pathway in liver cirrhosis. This study highlights the possibility of therapeutically targeting NRP-1 for the treatment of cirrhosis.

Funding: This work was supported by funds from National Natural Science Foundation of China (No. 81570551; 81770607; 81600469; 81401868), Key Research project of Shandong Province (No. 2016GSF201008; 2017GSF218053), Natural Science Foundation of Shandong Province (No. ZR2017MH102), National Science and Technology Major Project of China (No. 2018ZX10302206-001-006)

Declaration of Interest: The authors do not have a commercial or other association with pharmaceutical companies or other parties that might pose a conflict of interest.

Ethical Approval: All procedures were approved by the Ethics Committee of Shandong Provincial Hospital Affiliated to Shandong University (Jinan, China).

Keywords: neuropilin-1, vascular growth factor receptor 2, hepatic sinusoidal endothelial cells, intrahepatic angiogenesis, cirrhosis

Suggested Citation

Wang, Le and Feng, Yuemin and Xie, Xiaoyu and Wu, Hao and Su, Xiao nan and Qi, Jianni and Xin, Wei and Gao, Lifen and Zhang, Ying and Shah, Vijay H. and Zhu, Qiang, Neuropilin-1 Aggravates Liver Cirrhosis by Promoting Angiogenesis Via VEGFR2-Dependent PI3K/Akt Pathway in Hepatic Sinusoidal Endothelial Cells (March 8, 2019). Available at SSRN: https://ssrn.com/abstract=3349208

Le Wang

Shandong University - Department of Gastroenterology

Jinan, Shandong
China

Yuemin Feng

Shandong University - Department of Gastroenterology

Jinan, Shandong
China

Xiaoyu Xie

Shandong University - Department of Gastroenterology

Jinan, Shandong
China

Hao Wu

Shandong University - Department of Gastroenterology

Jinan, Shandong
China

Xiao nan Su

Shandong University - Department of Gastroenterology

Jinan, Shandong
China

Jianni Qi

Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control

Jinan, Shandong
China

Wei Xin

Shandong University - Shandong Provincial Hospital ( email )

China

Lifen Gao

Shandong University

27 Shanda Nanlu
South Rd.
Jinan, Shandong 250100
China

Ying Zhang

Johns Hopkins University - Department of Molecular Microbiology and Immunology

615 N. Wolfe Street
Baltimore, MD 21205
United States

Vijay H. Shah

Mayo Clinic and Mayo Foundation

Rochester, MN 55905
United States

Qiang Zhu (Contact Author)

Shandong University - Department of Gastroenterology ( email )

Jinan, Shandong
China

Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control ( email )

Jinan, Shandong
China

Click here to go to TheLancet.com

Go to TheLancet.com

Paper statistics

Abstract Views
58
Downloads
8