Vav1 is essential for HIF-1α activation in vascular response to ischemic stress

Vascular response to hypoxia is a major determinant of organ function under stress, which is particularly critical for vital organs such as the heart. This study identifies Vav1 as a key vascular regulator of hypoxia. Vav1 is present in vascular endothelium and is essential for HIF-1 activation under hypoxia. It regulates HIF-1α stabilization through the p38/Siah2/PHD3 pathway. Consequently, Vav1 deficient mice are predisposed to sudden death under cardiac ischemia with increased coronary endothelial apoptosis. Moreover, Vav1 binds to VEGFR1 that carries Vav1 to lysosomes for degradation in normoxia. Hypoxia upregulates Vav1 through inhibition of protein degradation. These findings reveal that regulation of Vav1 by hypoxia is analogous to HIF-1α regulation. Both proteins are constitutively produced allowing for rapid responses when stress occurs, and constantly degraded in normoxia. Hypoxia stabilizes Vav1, which is required for HIF-1α accumulation. Together they mediate the vascular response to hypoxia and maintain tissue homeostasis.