Endothelial responses to shear stress in atherosclerosis: a novel role for developmental genes

Flowing blood generates a frictional force called shear stress that has major effects on vascular function. Branches and bends of arteries are exposed to complex blood flow patterns that exert low or low oscillatory shear stress, a mechanical environment that promotes vascular dysfunction and atherosclerosis. Conversely, physiologically high shear stress is protective. Endothelial cells are critical sensors of shear stress but the mechanisms by which they decode complex shear stress environments to regulate physiological and pathophysiological responses remain incompletely understood. Several laboratories have advanced this field by integrating specialized shear-stress models with systems biology approaches, including transcriptome, methylome and proteome profiling and functional screening platforms, for unbiased identification of novel mechanosensitive signalling pathways in arteries. In this Review, we describe these studies, which reveal that shear stress regulates diverse processes and demonstrate that multiple pathways classically known to be involved in embryonic development, such as BMP–TGFβ, WNT, Notch, HIF1α, TWIST1 and HOX family genes, are regulated by shear stress in arteries in adults. We propose that mechanical activation of these pathways evolved to orchestrate vascular development but also drives atherosclerosis in low shear stress regions of adult arteries. The shear stress generated by flowing blood has major effects on vascular function, with low shear stress promoting vascular dysfunction and atherosclerosis. This Review describes the latest findings on how endothelial cells decode complex shear stress environments to regulate physiological and pathophysiological responses, highlighting the role of pathways involved in embryonic development. Key points Shear stress regulates atherosclerosis by altering endothelial cell physiology. Systems biology approaches have identified multiple shear stress-regulated pathways in the endothelium, including several pathways classically known to be involved in embryogenesis. Blood flow-mediated regulation of developmental pathways orchestrates valve formation and angiogenesis to optimize tissue perfusion. By contrast, in arteries in adults, these blood flow-regulated pathways lead to inflammation, vascular dysfunction and atherosclerosis.