2. Academic Validation
  3. Neuropilin-1 aggravates liver cirrhosis by promoting angiogenesis via VEGFR2-dependent PI3K/Akt pathway in hepatic sinusoidal endothelial cells

Neuropilin-1 aggravates liver cirrhosis by promoting angiogenesis via VEGFR2-dependent PI3K/Akt pathway in hepatic sinusoidal endothelial cells

  • EBioMedicine. 2019 May;43:525-536. doi: 10.1016/j.ebiom.2019.04.050.
Le Wang 1,  Yuemin Feng 1,  Xiaoyu Xie 1,  Hao Wu 1,  Xiao Nan Su 1,  Jianni Qi 2,  Wei Xin 3,  Lifen Gao 4,  Ying Zhang 5,  Vijay H Shah 6,  Qiang Zhu 7
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China; Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, Shandong Province, China.
  • 2 Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, Shandong Province, China; Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China.
  • 3 Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China.
  • 4 Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory for Infection and Immunity of Shandong Province, Department of Immunology School of Basic Medicine, Shandong University, Jinan, Shandong Province, China.
  • 5 Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
  • 6 Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN, USA.
  • 7 Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China; Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, Shandong Province, China. Electronic address: [email protected].
PMID: 31060904 DOI: 10.1016/j.ebiom.2019.04.050
Abstract

Background: We have revealed that neuropilin-1 (NRP-1) promoted hepatic stellate cell activation and liver fibrosis through its profibrogenic signalling pathways. However, the role of NRP-1 in angiogenesis in hepatic sinusoidal endothelial cells (HSECs) during liver cirrhosis remains unclear.

Methods: The correlation between NRP-1 expression and angiogenesis was evaluated in both human and murine cirrhotic liver tissues by immunohistochemical staining, quantitative Real-Time PCR, and western blotting. In addition, the role and mechanism of NRP-1 in regulating VEGFR2-dependent angiogenesis was identified in endothelial cells (ECs) in vitro. Moreover, liver histocultures were used to test the therapeutic effect of NRP-1 blocking in liver fibrosis.

Findings: Higher expression of NRP-1 in HSECs was detected, which was positively correlated with angiogenesis in liver cirrhosis. In vitro, NRP-1 knockdown suppressed the expression and activation of VEGFR2/KDR/Flk-1, accompanied by reduced ability of the vascular tube formation and the migration of ECs. Conversely, NRP-1 overexpression upregulated VEGFR2/KDR/Flk-1, promoted tube formation, and the migration of ECs. Mechanistically, NRP-1 modulated the expression of VEGFR2/KDR/Flk-1 by regulating FAK and its kinase activity. Furthermore, NRP-1 promoted VEGFR2-dependent angiogenesis via the PI3K/Akt pathway in HSECs. Blocking NRP-1 function reduced intrahepatic angiogenesis and fibrosis-associated factors in the in vitro liver histocultures.

Interpretation: NRP-1 promotes angiogenesis by upregulating the expression and activation of VEGFR2/KDR/Flk-1 through the PI3K/Akt signalling pathway in liver cirrhosis. This study highlights the possibility of therapeutically targeting NRP-1 for the treatment of cirrhosis. FUND: 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).

Keywords

Cirrhosis; Hepatic sinusoidal endothelial cells; Intrahepatic angiogenesis; Neuropilin-1; Vascular growth factor receptor 2.

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