Atherosclerosis occurs primarily at regions of the vasculature where bifurcations, turns or constrictions cause blood flow patterns to depart from the smooth, laminar mode and become disturbed, These results show that while systemic factors such as cholesterol or inflammatory mediators influence the progression of atherosclerosis, local hemodynamics play a crucial role. Yet our understanding of how endothelial cells sense and respond to fluid flow is limited, This proposal builds on recent advances in my lab showing that application of fluid flow (shear stress) to endothelial cells results in conversion of integrins to a high affinity state. The high affinity integrins then bind to extracellular matrix (ECM) proteins in the subendothelium and trigger activation of signaling pathways inside the cell, These integrin-dependent pathways are responsible for a significant subset of the responses to fluid shear stress, including cytoskeletal alignment and gene expression, In the present application, we propose first to elucidate the pathway by which fluid flow triggers integrin activation. Second. we will investigate whether binding of integrins to different subendothelial ECM proteins gives rise to distinct signals and responses to shear stress. Third, we will begin to dissect the difference between laminar and disturbed shear stress by investigating the nature of flow direction in the adaptation to flow at longer times. Taken together, these studies will substantially advance our basic understanding of how endothelial cells sense and respond to flowing blood.
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