Endothelial Gαq/11 is required for VEGF-induced vascular permeability and angiogenesis

Aims VEGF A (VEGF-A) is a central regulator of pre- and postnatal vascular development. In vitro studies suggested that heterotrimeric G-proteins of the G(q/11) family contribute to VEGF receptor 2 (VEGFR2) signalling, but the mechanism and physiological relevance of this finding is unknown. The aim of this study is to understand the role of endothelial G alpha(q/11) in VEGF-dependent regulation of vascular permeability and angiogenesis. Methods and results We show here that VEGF-A-induced signalling events, such as VEGFR2 autophosphorylation, calcium mobilization, or phosphorylation of Src and Cdh5, were reduced in G alpha(q/11)-deficient endothelial cells (ECs), resulting in impaired VEGF-dependent barrier opening, tube formation, and proliferation. Agonists at G(q/11)-coupled receptors facilitated VEGF-A-induced VEGFR2 autophosphorylation in a G alpha(q/11)-dependent manner, thereby enhancing downstream VEGFR2 signalling. In vivo, EC-specific G alpha(q/11)- and G alpha q-deficient mice showed reduced VEGF-induced fluid extravasation, and retinal angiogenesis was significantly impaired. G alpha q-deficient ECs showed reduced proliferation, Cdh5 phosphorylation, and fluid extravasation, whereas apoptosis was increased. Conclusion G alpha(q/11) critically contributes to VEGF-A-dependent permeability control and angiogenic behaviour in vitro and in vivo.