Abstract
Vascular endothelial growth factor A (VEGF-A) binds to the VEGFR2 receptor tyrosine kinase, regulating endothelial function, vascular physiology and angiogenesis. However, the mechanism underlying VEGFR2 turnover and degradation in this response is unclear. Here, we tested a role for heat-shock proteins in regulating the presentation of VEGFR2 to a degradative pathway. Pharmacological inhibition of HSP90 stimulated VEGFR2 degradation in primary endothelial cells and blocked VEGF-A-stimulated intracellular signaling via VEGFR2. HSP90 inhibition stimulated the formation of a VEGFR2-HSP70 complex. Clathrin-mediated VEGFR2 endocytosis is required for this HSP-linked degradative pathway for targeting VEGFR2 to the endosome-lysosome system. HSP90 perturbation selectively inhibited VEGF-A-stimulated human endothelial cell migration in vitro. A mouse femoral artery model showed that HSP90 inhibition also blocked blood vessel repair in vivo consistent with decreased endothelial regeneration. Depletion of either HSP70 or HSP90 caused defects in blood vessel formation in a transgenic zebrafish model. We conclude that perturbation of the HSP70-HSP90 heat-shock protein axis stimulates degradation of endothelial VEGFR2 and modulates VEGF-A-stimulated intracellular signaling, endothelial cell migration, blood vessel development and repair.
Highlights
Vascular endothelial growth factors (VEGFs) are a family of cytokines that bind cell surface receptors and regulate key steps in both physiological and pathological angiogenesis [1,2]
We investigated the role played by heatshock proteins (HSPs) in regulating the stability and turnover of VEGFR2 and subsequent Vascular endothelial growth factor A (VEGF-A)-regulated responses: intracellular signaling, endothelial cell migration and blood vessel repair
heat-shock protein of 90 kDa (HSP90) inhibition stimulated increased VEGFR2HSP70 complex formation that correlated with increased VEGFR2 degradation
Summary
Vascular endothelial growth factors (VEGFs) are a family of cytokines that bind cell surface receptors and regulate key steps in both physiological and pathological angiogenesis [1,2]. E.g. during tumor growth, synthesis of the VEGF-A isoform is increased, stimulating tumor neovascularization and enrichment of its oxygen and nutrient supply [1]. VEGF-A binds two structurally-related receptor tyrosine kinases on vascular endothelial cells: VEGF receptor 1 (VEGFR1, Flt-1) and 2 (VEGFR2, KDR, Flk-1). VEGFR2 largely mediates VEGF-A-induced pro-angiogenic signaling whereas VEGFR1 acts as a ‘decoy’ receptor that sequesters VEGF-A. Ligand binding to VEGFR2 promotes receptor dimerization and tyrosine kinase activation. This stimulates downstream signaling including activation of the cRaf/MEK/ERK and PI3K/Akt pathways leading to increased cell proliferation, migration and survival [2]
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