G13 Controls Angiogenesis through Regulation of VEGFR-2 Expression

•Endothelial G13 regulates VEGFR-2 promoter activity through NF-κB activation•Loss of endothelial G13 causes reduced VEGFR-2 expression and VEGF responsiveness•Endothelial G13 is required for retinal and tumor angiogenesis

SummaryAt sites of angiogenesis, the expression of the key angiogenesis regulator vascular endothelial growth factor (VEGF) and its main receptor, VEGF receptor 2 (VEGFR-2), are strongly upregulated. Whereas the processes controlling VEGF expression are well described, the mechanisms underlying VEGFR-2 upregulation have remained unclear. We found that endothelial VEGFR-2 expression is strongly reduced in the absence of the G protein G13, resulting in an impaired responsiveness to VEGF-A, a phenotype that can be rescued by normalization of VEGFR-2 levels. G13-mediated VEGFR-2 expression involved activation of the small GTPase RhoA and transcription factor NF-κB, the latter acting via a specific binding site at position −84 of the VEGFR-2 promoter. Mice with endothelial cell-specific loss of G13 showed reduced VEGFR-2 expression at sites of angiogenesis and attenuated VEGF effects, resulting in impaired retinal angiogenesis and tumor vascularization. Taken together, we identified G-protein-mediated signaling via G13 as a critical regulator of VEGFR-2 expression during angiogenesis.

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