Impact of hemodynamics on efferocytosis in endothelial cells

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PROJECT SUMMARY/ABSTRACT Flowing blood generates a frictional force called shear stress that plays an important role in endothelial dysfunction and atherosclerosis. Branches and bends of arteries are exposed to low and disturbed flow (d-flow), a mechanical environment that promotes vascular dysfunction and atherosclerosis. Conversely, physiologically high shear stress generated from steady laminar flow (s-flow) is protective. Helical flow (h-flow) associated with advanced shear stress exists not only in the ascending aorta but also in other parts such as the right coronary artery, descending aorta, common iliac artery, and common femoral artery. H-flow may have several positive physiological roles, such as suppressing/eliminating areas of flow stagnation, preventing the accumulation of atherogenic lipids on the luminal surfaces of arteries, and enhancing oxygen transport from the blood to the arterial wall. Endothelial cells (ECs) are critical sensors of the shear stress that contributes to atherosclerosis. Efferocytosis is a process by which apoptotic tissue is recognized for engulfment by phagocytic cells, such as professional phagocytes (e.g., macrophages and immature dendritic cells) and non-professional phagocytes (e.g., ECs, epithelial cells, fibroblasts, and some stromal cells). Defective efferocytosis in macrophages promotes advanced atherosclerosis. However, the mechanisms by which shear stress environments regulate EC efferocytosis and its implications in atherosclerosis remain largely unknown. The central hypothesis to be tested in this project is that blood flow patterns regulate EC efferocytosis and subsequent endothelial dysfunction and contribute to the development of atherosclerosis. Our long-term goal is to dissect the relationship between blood flow patterns and EC efferocytosis and its role in the development of atherosclerosis. Our specific aims are Aim 1- Define the role of blood flow patterns in EC efferocytosis and endothelial dysfunction, Aim 2- Determine the role of MerTK in endothelial mechanotransduction, and Aim 3- Evaluate the contribution of EC efferocytosis in atherosclerosis. Defining the mechanisms of efferocytosis regulation will be necessary to target endothelial mechanotransduction and subsequent endothelial dysfunction. The proposed research is innovative in the sense that we will connect blood flow patterns, EC efferocytosis, and endothelial mechanotransduction. We will also evaluate the novel mechanism of EC efferocytosis and its contribution to atherosclerosis.