Biomechanical regulation of endothelial function in atherosclerosis

Abstract Atherosclerosis is a chronic inflammatory disease of the arteries that is the underlying cause of heart attacks, ischemic strokes, and peripheral artery disease. Atherosclerosis preferentially occurs in curved and branching regions of the vasculature where endothelial cells experience low-magnitude and oscillatory shear stress from disturbed blood flow. Atherosclerosis rarely occurs in straight, unbranched regions of the vasculature where endothelial cells experience high-magnitude, unidirectional shear stress from stable blood flow. Disturbed flow induces proatherogenic endothelial responses, while stable flow triggers atheroprotective changes. In this review, we summarize the ways in which endothelial cells detect shear stress from blood flow, transmit these mechanical signals within the cell, and alter endothelial function by differentially expressing proteins, epigenetic modifiers, and noncoding RNAs in response to disturbed and stable flow. We then review major endothelial functions regulated by flow, such as inflammation and endothelial to mesenchymal transition. Finally, we describe flow-sensitive proteins, such as hypoxia-inducible factor 1alpha and Kruppel-like factor 2 and 4, epigenetic modifiers, such as DNA methyl transferases and histone deacetylases, as well as microRNAs and long noncoding RNAs. A thorough understanding of the ways by which disturbed blood flow alters endothelial function to promote atherosclerosis will help to identify novel therapeutic targets for the treatment of this perilous disease.