Neuropilin-1 aggravates liver cirrhosis by promoting angiogenesis via VEGFR2-dependent PI3K/Akt pathway in hepatic sinusoidal endothelial cells
| Autor: | Hao Wu, Ying Zhang, Yuemin Feng, Xiao Nan Su, Jianni Qi, Le Wang, Wei Xin, Xiaoyu Xie, Lifen Gao, Vijay H. Shah, Qiang Zhu |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
CD31
0301 basic medicine Liver Cirrhosis Cirrhosis Research paper Angiogenesis Gene Expression Models Biological General Biochemistry Genetics and Molecular Biology Cell Line Tissue Culture Techniques 03 medical and health sciences Mice Phosphatidylinositol 3-Kinases 0302 clinical medicine Neuropilin 1 medicine Animals Humans Kinase activity PI3K/AKT/mTOR pathway Liver injury Tube formation Gene knockdown Neovascularization Pathologic business.industry Akt/PKB signaling pathway Chemistry Endothelial Cells General Medicine medicine.disease Hepatic stellate cell activation Vascular Endothelial Growth Factor Receptor-2 Neuropilin-1 030104 developmental biology 030220 oncology & carcinogenesis Cancer research business Proto-Oncogene Proteins c-akt Signal Transduction |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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