Vinculin associates with endothelial VE-cadherin junctions to control force-dependent remodeling

TLDR

Endothelial cell‑cell adhesion remodeling is driven by inflammatory cytokine and angiogenic growth factor signals that target the VE‑cadherin complex, the central component of adherens junctions, and occurs at focal adherens junctions (FAJs) that are attached to radial F‑actin bundles and marked by the mechanosensory protein Vinculin. Actin‑generated pulling forces on FAJs, mediated by Rho‑Rock‑actomyosin contractility, drive junction remodeling, and inhibiting this contractility blocks FAJ formation. The study shows that inflammatory hormones such as VEGF, TNF‑α, and thrombin convert stable junctions into FAJs, that Vinculin recruitment is dispensable for FAJ formation but protects VE‑cadherin from opening during force‑dependent remodeling, implicating Vinculin‑dependent mechanosensing in leukocyte extravasation and angiogenesis.

Abstract

To remodel endothelial cell-cell adhesion, inflammatory cytokine- and angiogenic growth factor-induced signals impinge on the vascular endothelial cadherin (VE-cadherin) complex, the central component of endothelial adherens junctions. This study demonstrates that junction remodeling takes place at a molecularly and phenotypically distinct subset of VE-cadherin adhesions, defined here as focal adherens junctions (FAJs). FAJs are attached to radial F-actin bundles and marked by the mechanosensory protein Vinculin. We show that endothelial hormones vascular endothelial growth factor, tumor necrosis factor α, and most prominently thrombin induced the transformation of stable junctions into FAJs. The actin cytoskeleton generated pulling forces specifically on FAJs, and inhibition of Rho-Rock-actomyosin contractility prevented the formation of FAJs and junction remodeling. FAJs formed normally in cells expressing a Vinculin binding-deficient mutant of α-catenin, showing that Vinculin recruitment is not required for adherens junction formation. Comparing Vinculin-devoid FAJs to wild-type FAJs revealed that Vinculin protects VE-cadherin junctions from opening during their force-dependent remodeling. These findings implicate Vinculin-dependent cadherin mechanosensing in endothelial processes such as leukocyte extravasation and angiogenesis.