Hypoxia differentially regulates VEGFR1 and VEGFR2 levels and alters intracellular signaling and cell migration in endothelial cells

The role of hypoxia on endothelial cell function and response to growth factors is unknown. Here, we tested the hypothesis that hypoxia re-programs endothelial function by modulating vascular endothelial growth factor receptor levels which in turn alter intracellular signaling and cell function. Hypoxia stimulated VEGF-A and VEGFR1 expression but decreased VEGFR2 levels in endothelial cells. During hypoxia, plasma membrane VEGFR1 levels were elevated whereas VEGFR2 levels were depleted. One functional consequence of hypoxia is a reduction in VEGF-A-stimulated and VEGFR2-regulated intracellular signaling including lowered endothelial nitric oxide synthase activation. Venous, arterial and capillary endothelial cells subjected to hypoxia all exhibited reduced cell migration in response to VEGF-A. A mechanistic explanation is that VEGFR1:VEGFR2 ratio is substantially increased during hypoxia to block VEGF-A-stimulated and VEGFR2-regulated endothelial responses to maximize cell viability and recovery.

Research highlights
► In primary endothelial cells, hypoxia stimulates VEGF-A and VEGFR1 expression but decreases VEGFR2 levels.
► Hypoxia inhibits VEGF-A-stimulated and VEGFR2-regulated intracellular signaling including endothelial nitric oxide synthase activation.
► Venous, arterial and capillary endothelial cells all exhibited reduced VEGF-A-stimulated cell migration under hypoxia.
► An elevated VEGFR1:VEGFR2 ratio thus blocks VEGF-A-regulated endothelial responses to maximize cell viability and recovery from hypoxia.