Autocrine VEGF Regulates Fluid Shear Responses in Endothelial Cells

VEGFR2 was previously reported to mediate ligand‐independent activation on endothelial cells by fluid shear stress. More recently it has been shown that endothelial cells express VEGFA, which plays a critical autocrine role in regulating endothelial function. Here we tested the hypothesis that autocrine VEGFA mediates VEGFR2 activation and downstream signaling by shear stress. Down‐regulation of VEGFA by siRNA transfection in primary endothelial cells attenuated phosphorylation of VEFR2, Akt, Src and eNOS. Heparan sulfate proteoglycans (HSPG) function as co‐receptors to VEGFR2. Disruption of HSPGs by heparinase III or sodium chlorate treatment attenuated flow responses. Overexpression of VEGFA189, an isoform with a strong heparan sulfate binding domain, enhanced the flow response. Taken together, evidence is provided that VEGFR2 activation by shear stress is not ligand‐independent and is mediated by VEGFA through an autocrine mechanism.