Cholesterol crystals increase vascular permeability by inactivating SHP2 and disrupting adherens junctions

Abstract

To understand the adverse effects of cholesterol crystals on vascular homeostasis, we have studied their effects on endothelial barrier function. Cholesterol crystals increased endothelial barrier permeability in a dose and time dependent manner. In addition, cholesterol crystals induced tyrosine phosphorylation of VE-cadherin and α-catenin, disrupting endothelial AJ and its barrier function and these effects required xanthine oxidase-mediated H₂O₂ production, SHP2 inactivation and Frk activation. Similarly, feeding C57BL/6 mice with cholesterol-rich diet increased xanthine oxidase expression, H₂O₂ production, SHP2 inactivation and Frk activation leading to enhanced tyrosine phosphorylation of VE-cadherin and α-catenin, thereby disrupting endothelial AJ and increasing vascular permeability. Resolvin D1, a specialized proresolving mediator, prevented all these adverse effects of cholesterol crystals and cholesterol-rich diet in endothelial cells and mice, respectively. Based on these observations, it is likely that cholesterol crystals via disrupting AJ increase vascular permeability, a critical event of endothelial dysfunction and specialized proresolving mediators such as Resolvin D1 exert protection against these effects.

Keywords: Adherens junctions; Cholesterol crystals; H2O2; SHP2; Vascular permeability.