Fluid Shear Stress–Regulated Vascular Remodeling: Past, Present, and Future

The vascular system remodels throughout life to ensure adequate perfusion of tissues as they grow, regress, or change metabolic activity. Angiogenesis, the sprouting of new blood vessels to expand the capillary network, versus regression, in which endothelial cells die or migrate away to remove unneeded capillaries, controls capillary density. In addition, upstream arteries adjust their diameters to optimize blood flow to downstream vascular beds, which is controlled primarily by vascular endothelial cells sensing fluid shear stress (FSS) from blood flow. Changes in capillary density and small artery tone lead to changes in the resistance of the vascular bed, which leads to decreased or increased flow through the arteries that feed these small vessels. The resultant changes in FSS through these vessels then stimulate their inward or outward remodeling, respectively. This review summarizes our knowledge of endothelial FSS–dependent vascular remodeling, offering insights into potential therapeutic interventions. We first provide a historical overview, then discuss the concept of set point and mechanisms of low-FSS–mediated and high-FSS–mediated inward and outward remodeling. We then cover in vivo animal models, molecular mechanisms, and clinical implications. Understanding the mechanisms underlying physiological endothelial FSS–mediated vascular remodeling and their failure due to mutations or chronic inflammatory and metabolic stresses may lead to new therapeutic strategies to prevent or treat vascular diseases.