Regulation of endothelial cell activity and vascular inflammation by shear stress

Abstract

Atherosclerosis, a chronic inflammatory disease of arteries, develops predominantly at branches, bends, and bifurcations in the arterial tree that are exposed to low or disturbed blood flow. The endothelium is in direct contact with flowing blood and hence is exposed to shear stress, a mechanical force that varies with time, magnitude, and direction, according to vascular pulsatility and anatomy. Bends and bifurcations of arteries that are susceptible to lesion formation are exposed to low/oscillatory shear stress, a mechanical environment that influences vascular physiology by enhancing inflammatory activation and promoting endothelial cell (EC) apoptosis. In contrast, relatively straight, unbranched regions of the arterial tree that are exposed to high shear stress are protected from inflammation, EC death and lesion development. Thus low shear stress may predispose arteries for lesion formation whereas high shear stress may prevent atherosclerosis by enhancing endothelial protection. In this paper, I will summarize some of the molecular mechanisms behind the spatial localization of vascular inflammation and atherosclerosis, emphasizing studies by my research group of two key proinflammatory signaling pathways, the mitogen-activated protein kinase (MAPK) pathway and the nuclear factor-kappa-B (NF-κB) pathway.