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

Le Wang, Yuemin Feng, Xiaoyu Xie, Hao Wu, Xiao Nan Su, Jianni Qi, Wei Xin, Lifen Gao, Ying Zhang, Vijay Shah, Qiang Zhu

Research output: Contribution to journalArticle

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, accompanied by reduced ability of the vascular tube formation and the migration of ECs. Conversely, NRP-1 overexpression upregulated VEGFR2, promoted tube formation, and the 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 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 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).

Original languageEnglish (US)
JournalEBioMedicine
DOIs
StatePublished - Jan 1 2019

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Neuropilin-1
Endothelial cells
Phosphatidylinositol 3-Kinases
Liver Cirrhosis
Liver
Endothelial Cells
Natural Science Disciplines
Natural sciences
Chemical activation
China
Fibrosis
Hepatic Stellate Cells
Therapeutic Uses

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Neuropilin-1 aggravates liver cirrhosis by promoting angiogenesis via VEGFR2-dependent PI3K/Akt pathway in hepatic sinusoidal endothelial cells. / Wang, Le; Feng, Yuemin; Xie, Xiaoyu; Wu, Hao; Su, Xiao Nan; Qi, Jianni; Xin, Wei; Gao, Lifen; Zhang, Ying; Shah, Vijay; Zhu, Qiang.

In: EBioMedicine, 01.01.2019.

Research output: Contribution to journalArticle

Wang, Le ; Feng, Yuemin ; Xie, Xiaoyu ; Wu, Hao ; Su, Xiao Nan ; Qi, Jianni ; Xin, Wei ; Gao, Lifen ; Zhang, Ying ; Shah, Vijay ; Zhu, Qiang. / Neuropilin-1 aggravates liver cirrhosis by promoting angiogenesis via VEGFR2-dependent PI3K/Akt pathway in hepatic sinusoidal endothelial cells. In: EBioMedicine. 2019.
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title = "Neuropilin-1 aggravates liver cirrhosis by promoting angiogenesis via VEGFR2-dependent PI3K/Akt pathway in hepatic sinusoidal endothelial cells",
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, accompanied by reduced ability of the vascular tube formation and the migration of ECs. Conversely, NRP-1 overexpression upregulated VEGFR2, promoted tube formation, and the 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 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 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",
author = "Le Wang and Yuemin Feng and Xiaoyu Xie and Hao Wu and Su, {Xiao Nan} and Jianni Qi and Wei Xin and Lifen Gao and Ying Zhang and Vijay Shah and Qiang Zhu",
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T1 - Neuropilin-1 aggravates liver cirrhosis by promoting angiogenesis via VEGFR2-dependent PI3K/Akt pathway in hepatic sinusoidal endothelial cells

AU - Wang, Le

AU - Feng, Yuemin

AU - Xie, Xiaoyu

AU - Wu, Hao

AU - Su, Xiao Nan

AU - Qi, Jianni

AU - Xin, Wei

AU - Gao, Lifen

AU - Zhang, Ying

AU - Shah, Vijay

AU - Zhu, Qiang

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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, accompanied by reduced ability of the vascular tube formation and the migration of ECs. Conversely, NRP-1 overexpression upregulated VEGFR2, promoted tube formation, and the 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 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 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).

AB - 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, accompanied by reduced ability of the vascular tube formation and the migration of ECs. Conversely, NRP-1 overexpression upregulated VEGFR2, promoted tube formation, and the 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 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 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).

KW - Cirrhosis

KW - Hepatic sinusoidal endothelial cells

KW - Intrahepatic angiogenesis

KW - Neuropilin-1

KW - Vascular growth factor receptor 2

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