At 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.