神经纤毛蛋白-1 通过激活血管内皮生长因子受体 2 依赖的磷脂酰肌醇 3-激酶/蛋白激酶 B 通路促进肝窦内皮细胞血管生成加重肝纤维化。
Neuropilin-1 aggravates liver cirrhosis by promoting angiogenesis via VEGFR2-dependent PI3K/Akt pathway in hepatic sinusoidal endothelial cells.
机构信息
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.
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.
出版信息
EBioMedicine. 2019 May;43:525-536. doi: 10.1016/j.ebiom.2019.04.050. Epub 2019 May 3.
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).
背景
我们已经揭示了神经纤毛蛋白-1（NRP-1）通过其促纤维化信号通路促进肝星状细胞激活和肝纤维化。然而，NRP-1 在肝硬化时肝窦内皮细胞（HSEC）中的血管生成中的作用尚不清楚。
方法
通过免疫组织化学染色、实时定量 PCR 和 Western blot 评估了 NRP-1 表达与人及鼠肝硬化肝组织中血管生成的相关性。此外，在体外内皮细胞（ECs）中鉴定了 NRP-1 调节 VEGFR2 依赖性血管生成的作用和机制。此外，还使用肝组织培养物来测试 NRP-1 阻断在肝纤维化中的治疗效果。
发现
在 HSEC 中检测到更高表达的 NRP-1，其与肝硬化中的血管生成呈正相关。在体外，NRP-1 敲低抑制了 VEGFR2 的表达和激活，伴随着 ECs 的血管形成和迁移能力的降低。相反，NRP-1 过表达上调了 VEGFR2，促进了 ECs 的管形成和迁移。在机制上，NRP-1 通过调节 FAK 及其激酶活性来调节 VEGFR2 的表达。此外，NRP-1 通过 PI3K/Akt 通路在 HSEC 中促进 VEGFR2 依赖性血管生成。阻断 NRP-1 功能减少了体外肝组织培养物中的肝内血管生成和纤维化相关因子。
解释
NRP-1 通过 PI3K/Akt 信号通路上调 VEGFR2 的表达和激活，从而促进肝硬化中的血管生成。本研究强调了针对 NRP-1 治疗肝硬化的可能性。
资助
国家自然科学基金（No. 81570551; 81770607; 81600469; 81401868），山东省重点研发计划（No. 2016GSF201008; 2017GSF218053），山东省自然科学基金（No. ZR2017MH102），国家科技重大专项（No. 2018ZX10302206-001-006）。
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