Journal
THERANOSTICS
Volume 8, Issue 17, Pages 4695-4709Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.26203
Keywords
VEGFR2; G alpha i1; G alpha i3; endocytosis; angiogenesis; signaling
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Funding
- National Natural Science Foundation of China [81302195, 31371139, 81571282, 81771457, 81700859, 81371055, 81570859, 81502162, 81670878]
- Medical Science and Technology Development Project Fund of Nanjing [YKK16271, YKK15241, YKK16270]
- Natural Science Foundation of Jiangsu Province [BK20161568, BK20170060, BK20171065]
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VEGF binding to VEGFR2 leads to VEGFR2 endocytosis and downstream signaling activation to promote angiogenesis. Methods: Using genetic strategies, we tested the requirement of a subunits of heterotrimeric G proteins (G alpha i1/3) in the process. Results: G alpha i1/3 are located in the VEGFR2 endocytosis complex (VEGFR2-Ephrin-B2-Dab2-PAR-3), where they are required for VEGFR2 endocytosis and downstream signaling transduction. G alpha i1/3 knockdown, knockout or dominant negative mutation inhibited VEGF-induced VEGFR2 endocytosis, and downstream Akt-mTOR and Erk-MAPK activation. Functional studies show that G alpha i1/3 shRNA inhibited VEGF-induced proliferation, invasion, migration and vessel-like tube formation of HUVECs. In vivo, G alpha i1/3 shRNA lentivirus inhibited alkali burn-induced neovascularization in mouse cornea. Further, oxygen-induced retinopathy (OIR)-induced retinal neovascularization was inhibited by intravitreal injection of G alpha i1/3 shRNA lentivirus. Moreover, in vivo angiogenesis by alkali burn and OIR was significantly attenuated in G alpha i1/3 double knockout mice. Significantly, G alpha i1/3 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 G alpha i1/3 proteins in VEGF-induced VEGFR2 endocytosis, signaling and angiogenesis.
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