Blood flow patterns directly determine where artery-clogging plaques form—straight, steady-flow segments stay healthy, while branches and curves with disturbed flow become disease hotspots. This matters because the molecular machinery that lets blood vessel lining cells sense and respond to these mechanical forces remains poorly understood. Without knowing exactly how cells convert the physical push of blood into chemical signals, researchers cannot design drugs to interrupt the inflammatory cascade that leads to atherosclerosis, the underlying cause of most heart attacks and strokes. The team has already identified a key sensor—a protein complex called PECAM-1 that sits on the surface of endothelial cells. This project tests whether mechanical force on PECAM-1 triggers a specific chain of molecular events that switches on disease-promoting signals inside blood vessel walls. If successful, it will reveal precise targets for new therapies that could slow or prevent chronic inflammation and atherosclerosis by blocking the mechanical-to-chemical conversion at its source. This is fundamental science with clear translational potential. Understanding how a physical force becomes a pathological signal could eventually lead to drugs that protect vulnerable artery regions without requiring patients to change their blood flow patterns.
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Haemodynamic forces are integral regulators of proper vascular function, but they are also potent instigators of disease processes. The mechanical stimulus of shear stress due to fluid flow is a critical determinant of vessel function: regions of arteries that are subjected to low and disturbed flow are prone 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) sense and respond to shear stress and the mechanisms by which disturbed shear stress leads 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 results in activation of pathological signaling in ECs and blood vessels in vivo. Completion of the proposed work will not only provide novel insights into the process 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.
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