Endothelial shear stress signal transduction and atherogenesis: From mechanisms to therapeutics

Atherosclerotic vascular disease and its complications are among the top causes of mortality worldwide. In the vascular lumen, atherosclerotic plaques are not randomly distributed. Instead, they are preferentially localized at the curvature and bifurcations along the arterial tree, where shear stress is low or disturbed. Numerous studies demonstrate that endothelial cell phenotypic change (e.g., inflammation, oxidative stress, endoplasmic reticulum stress, apoptosis, autophagy, endothelial-mesenchymal transition, endothelial permeability, epigenetic regulation, and endothelial metabolic adaptation) induced by oscillatory shear force play a fundamental role in the initiation and progression of atherosclerosis. Mechano-sensors, adaptor proteins, kinases, and transcriptional factors work closely at different layers to transduce the shear stress force from the plasma membrane to the nucleus in endothelial cells, thereby controlling the expression of genes that determine cell fate and phenotype. An in-depth understanding of these mechano-sensitive signaling cascades shall provide new translational strategies for therapeutic intervention of atherosclerotic vascular disease. This review updates the recent advances in endothelial mechano-transduction and its role in the pathogenesis of atherosclerosis, and highlights the perspective of new anti-atherosclerosis therapies through targeting these mechano-regulated signaling molecules.