Coxsackievirus and adenovirus receptor mediates the responses of endothelial cells to fluid shear stress

Abstract

Endothelial mechanotransduction by fluid shear stress (FSS) modulates endothelial function and vascular pathophysiology through mechanosensors on the cell membrane. The coxsackievirus and adenovirus receptor (CAR) is not only a viral receptor but also a component of tight junctions and plays an important role in tissue homeostasis. Here, we demonstrate the expression, regulatory mechanism, and role of CAR in vascular endothelial cells (ECs) under FSS conditions. Disturbed flow increased, whereas unidirectional laminar shear stress (LSS) decreased, CAR expression in ECs through the Krüppel-like factor 2 (KLF2)/activator protein 1 (AP-1) axis. Deletion of CAR reduced the expression of proinflammatory genes and endothelial inflammation induced by disturbed flow via the suppression of NF-κB activation. Consistently, disturbed flow-induced atherosclerosis was reduced in EC-specific CAR KO mice. CAR was found to be involved in endothelial mechanotransduction through the regulation of platelet endothelial cell adhesion molecule 1 (PECAM-1) phosphorylation. Our results demonstrate that endothelial CAR is regulated by FSS and that this regulated CAR acts as an important modulator of endothelial mechanotransduction by FSS.

Vascular disease: Blood flow disturbances and atherosclerosis

Research into the mechanisms by which blood flow disturbances affect the function of endothelial cells (ECs), the cells lining the interior of blood vessels, reveals potential new targets for treating atherosclerosis. Kihwan Kwon at Ewha Womans University in Seoul, South Korea, and colleagues found that a membrane protein, the coxsackie and adenovirus receptor, CAR, mediates the response of ECs to the shear stress exerted by blood flow. They showed, in human tissue and in mice, that CAR protein levels in ECs increase when they are exposed to low or oscillatory blood flow, which is linked to the build-up of plaque inside arteries. Lowering CAR levels in ECs reduced the expression of proinflammatory genes and the formation of atherosclerotic lesions in mice. These findings suggest that reducing CAR activity could be a promising approach for treating atherosclerosis.