Role of shear-stress-induced VEGF expression in endothelial cell survival

TLDR

VEGF is essential for angiogenesis and is expressed in quiescent adult tissues, suggesting it helps maintain mature blood vessels. In vitro, arterial shear stress on HUVECs reduces apoptosis and upregulates VEGF via KLF2, while also inducing VEGFR2 expression and activation. The study shows arterial ECs express VEGF and that arterial shear stress protects endothelial cells from apoptosis through VEGF–VEGFR2 autocrine signaling, as loss of VEGF or VEGFR2 signaling abolishes this protection.

Abstract

Vascular endothelial growth factor (VEGF) plays a crucial role in developmental and pathological angiogenesis. Expression of VEGF in quiescent adult tissue suggests a potential role in the maintenance of mature blood vessels. We demonstrate, using a Vegf–lacZ reporter mouse model, that VEGF is expressed by arterial but not by venous or capillary endothelial cells (ECs) in vivo. Using an in vitro model, we show that arterial shear stress of human umbilical vein ECs (HUVECs) decreases apoptosis and increases VEGF expression, which is mediated by the induction of Krüppel-like factor 2 (KLF2). Additionally, shear stress stimulates the expression of VEGF receptor 2 (VEGFR2) and is associated with its activation. Knockdown of VEGF in shear stressed HUVECs blocks the protective effect of shear stress, resulting in EC apoptosis equivalent to that in control ECs cultured under static conditions. Similarly, treatment of ECs subjected to arterial shear stress with the VEGF receptor tyrosine kinase inhibitor SU1498, or VEGFR2 neutralizing antiserum, led to increased apoptosis, demonstrating that the mechanoprotection from increased shear is mediated by VEGFR2. Taken together, these studies suggest that arterial flow induces VEGF–VEGFR2 autocrine–juxtacrine signaling, which is a previously unidentified mechanism for vascular EC survival in adult arterial blood vessels.