Gαi1 and Gαi3mediate VEGF-induced VEGFR2 endocytosis, signaling and angiogenesis.
Gαi1 and Gαi3mediate VEGF-induced VEGFR2 endocytosis, signaling and angiogenesis.
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G α i1 和 G α i3 介导 VEGF 诱导的 VEGFR2 内吞作用、信号传导和血管生成
作者：
Sun J;Huang W;Yang SF;Zhang XP;Yu Q;Zhang ZQ;Yao J;Li KR;Jiang Q;Cao C
VEGF与VEGFR2结合，导致VEGFR2内吞和下游信号激活，促进血管生成。方法：采用遗传策略检测异源三聚体G蛋白α亚基（Gα 1/3）的需要量。结果：Gαi1/3位于VEGFR2内吞复合物（VEGFR2- ephrin - b2- dab2 - par -3）中，是VEGFR2内吞和下游信号转导所必需的。Gαi1/3敲低、敲除或显性负突变抑制vegf诱导的VEGFR2内吞，抑制下游Akt-mTOR和Erk-MAPK的激活。功能研究表明，g - α 1/3 shRNA可抑制vegf诱导的HUVECs增殖、侵袭、迁移和血管样管形成。在体内，g α 1/3 shRNA慢病毒抑制碱烧伤诱导的小鼠角膜新生血管形成。此外，玻璃体内注射g α 1/3 shRNA慢病毒可抑制氧诱导视网膜病变（OIR）诱导的视网膜新生血管形成。此外，碱烧伤和OIR对g α 1/3双敲除小鼠体内血管生成的影响也明显减弱。g α 1/3蛋白在增殖性糖尿病视网膜病变（PDR）患者的增殖性视网膜组织中表达上调。结论：这些结果为g α 1/3蛋白在vegf诱导的VEGFR2内吞、信号传导和血管生成中所起的关键作用提供了机制见解。
VEGF binding to VEGFR2 leads to VEGFR2 endocytosis and downstream signaling activation to promote angiogenesis. Methods: Using genetic strategies, we tested the requirement of α subunits of heterotrimeric G proteins (Gαi1/3) in the process. Results: Gαi1/3 are located in the VEGFR2 endocytosis complex (VEGFR2-Ephrin-B2-Dab2-PAR-3), where they are required for VEGFR2 endocytosis and downstream signaling transduction. Gαi1/3 knockdown, knockout or dominant negative mutation inhibited VEGF-induced VEGFR2 endocytosis, and downstream Akt-mTOR and Erk-MAPK activation. Functional studies show that Gαi1/3 shRNA inhibited VEGF-induced proliferation, invasion, migration and vessel-like tube formation of HUVECs. In vivo, Gαi1/3 shRNA lentivirus inhibited alkali burn-induced neovascularization in mouse cornea. Further, oxygen-induced retinopathy (OIR)-induced retinal neovascularization was inhibited by intravitreal injection of Gαi1/3 shRNA lentivirus. Moreover, in vivo angiogenesis by alkali burn and OIR was significantly attenuated in Gαi1/3 double knockout mice. Significantly, Gαi1/3 proteins are upregulated in proliferative retinal tissues of proliferative diabetic retinopathy (PDR) patients. Conclusion: These results provide mechanistic insights into the critical role played by Gαi1/3 proteins in VEGF-induced VEGFR2 endocytosis, signaling and angiogenesis.