Structured Graphical Abstract.

Proposed mechanisms by which disturbed flow induces vinculin phosphorylation at serine 721 (VCL^S721p) in vascular endothelium, leading to atherosclerosis. A combination of porcine models, large-scale phosphoproteomics, transgenic mice, and clinical specimens was used to demonstrate that disturbed flow induces endothelial VCL^S721p via G-protein-coupled receptor kinase 2 (GRK2)^S29p, resulting in an inactive form of VCL with a closed conformation. This disrupted the VE-cadherin junction/catenin complex to enhance endothelial permeability and atherosclerosis. Statin therapy was associated with reduced levels of sVCL^S721p and sVCL^S721p/sVCL in the serum of patients with coronary artery disease. Thus, endothelial VCL^S721p and serum levels of sVCL^S721p and sVCL^S721p/sVCL are promising molecular targets for the clinical assessment and treatment of atherosclerosis. AJ, adherens junction.