Phosphorylation of VE-cadherin is modulatedby haemodynamic forces and contributes to theregulation of vascular permeability in vivo

摘要

Endothelial adherens junctions maintain vascular integrity. Arteries and veins differ in theirpermeability but whether organization and strength of their adherens junctions vary has notbeen demonstrated in vivo. Here we report that vascular endothelial cadherin, an endothelialspecific adhesion protein located at adherens junctions, is phosphorylated in Y658 and Y685in vivo in veins but not in arteries under resting conditions. This difference is due to shearstress-induced junctional Src activation in veins. Phosphorylated vascular endothelial-cadherin is internalized and ubiquitinated in response to permeability-increasing agents such asbradykinin and histamine. Inhibition of Src blocks vascular endothelial cadherin phosphorylation and bradykinin-induced permeability. Point mutation of Y658F and Y685F preventsvascular endothelial cadherin internalization, ubiquitination and an increase in permeability bybradykinin in vitro. Thus, phosphorylation of vascular endothelial cadherin contributes to adynamic state of adherens junctions, but is not sufficient to increase vascular permeability inthe absence of inflammatory agents.