Vinculin phosphorylation modulates endothelial cell permeability: a new target for cardiovascular disease?

In athero-resistant vessels, the pulsatile, laminar shear stress restrains vinculin (VCL) in an active open conformation that allows the interaction of its head and tail with adaptor ligands preserving vascular endothelial (VE) junctions and in turn endothelial barrier integrity. In athero-susceptible regions, the turbulent and vicious blood flow induces post-translational modification of VCL which becomes highly phosphorylated at Ser721, resulting in the modification of the protein conformation towards the closed form with a poor interaction with VE-cadherin, thus influencing endothelial barrier integration and favouring progression of atherosclerosis. Phosphorylated (i.e. active) GRK2 promotes VCL phosphorylation, and its inhibition could be a potential approach to limit VCLS721 phosphorylation, improve endothelial function, and limit atherogenesis.