Mechanotransduction in Physiology and Cardiovascular Disease. (360G-Wellcome-100980_C_13_Z)

Haemodynamic forces are integral regulators of proper vascular function, but they are also potent instigators of disease processes. The mechanical stimulusof shear stress due to fluid flow is a critical determinant of vessel function: regions of arteries that are subjected to low and disturbed flow areprone to development of atherosclerotic plaques; in contrast, pulsatile flow in straight segments of arteries exerts a protective effect on the vessel wall. Despite the importance of mechanotra nsduction in vascular function and pathology, the molecular mechanisms by which endothelial cells (ECs) senseand respond to shear stress and the mechanisms by which disturbed shear stressleads to chronic inflammation and atherosclerosis are still not well understood. The EC surface is equipped with numerous mechanoreceptors or mechanosensors that are capable of sensing the mechanical stimulus of shear stress and converting it into biochemical signaling pathways inside the cell. Our own work ha s identified a mechanosensory complex consisting of PECAM-1 that is required for EC responses to shear stress in vitro and flow-mediated remodeling in vivo. The current project will use our expertise in bioengineering, cell biology and physiology to test the hypothesis that mechanical force on PECAM-1 elicits a mechanotransduction cascade that resultsin activation of pathological signaling in ECs and blood vessels in vivo. Completion of the proposed work will not only provide novel insights into theprocess of mechanotransduction in the vessel wall, but will identify urgently needed therapies for altering the course of mechanically-mediated diseases, such as chronic inflammation and atherosclerosis.