Direct evidence for the role of PECAM‐1 in mechanotransduction and vascular remodeling

Abstract

Flow‐induced shear stress plays an important role in the development of the vasculature, the maintenance of vascular integrity and vascular diseases, such as atherosclerosis. Disturbed flows near bifurcations and curvatures are associated with increased inflammation, leukocyte adhesion and atheroma formation. We have previously shown that platelet endothelial cell adhesion molecule‐1(PECAM‐1) plays an important role in mechanotransduction. Here, we investigate the role of PECAM‐1 in flow‐induced inflammation and flow‐mediated remodeling. PECAM‐1 knockout (KO) and reconstituted (RC) endothelial cells were subjected to oscillatory flow and their inflammatory response was assayed. Oscillatory flow induced sustained NF‐kB activation in endothelial cells expressing PECAM‐1; however this was not seen in KO endothelial cells. Prolonged oscillatory flow in RC cells promoted expression of the cell adhesion molecules ICAM‐1 and VCAM‐1, which resulted in increased leukocyte adhesion to the endothelium. These effects were significantly dampened in cells that lacked PECAM‐1. To test the role of PECAM‐1 in flow‐mediated remodeling in vivo, we performed partial ligation of the left carotid artery in PECAM‐1‐null and wild‐type mice. Importantly, we observed NF‐kB activation, increased ICAM‐1 and VCAM‐1 expression, intima‐media thickening of the left carotid artery and leukocyte transmigration in wild‐type mice. In contrast, the PECAM‐1 null mice showed no activation of NF‐kB, reduced expression of ICAM‐1 and VCAM‐1 and substantially decreased remodeling. These observations indicate that disturbed shear stress activates NF‐kB and inflammatory responses through PECAM‐1 in endothelial cells. These effects further induce arterial remodeling in vivo. Therefore, we conclude that disturbed shear stress initiates atherogenesis and vascular remodeling in vivo through PECAM‐1.