The shear stress due to blood flow is borne primarily by endothelial cells (ECs) located at the interface between blood and vessel wall. Atherosclerotic lesions are preferentially localized in regions such as arterial branch points and local lumen expansions, where the ECs are subjected to disturbed flow conditions, including flow reattachment, low shear stress magnitude, high shear stress gradient, and little net direction of flow. The ECs in these regions have different structural and functional characteristics in comparison to those in the straight parts of the arterial tree, which are exposed to pulsatile flow with a large net forward direction. Our Hypothesis is that flows with a significant net direction cause adaptive changes in cell morphology to reduce surface stress and alter molecular signaling, such that the ECs can optimize their functions. In contrast, disturbed flows without a significant net direction do not elicit the same adaptive effects on EC surface stress distribution and lead to different spatial and temporal characteristics of molecular signaling, structural remodeling, and mechanical properties, thus resulting in distinct functional consequences such as vulnerability to atherosclerosis. The following five Specific Aims are proposed to test our hypothesis by using a combination of in vitro (first three Specific Aims), ex vivo and in vivo approaches: (1) To determine the effects of different shear flow patterns on surface stress and structural remodeling of ECs. (2) To elucidate the interplays between EC remodeling and molecular signaling in response to different shear flow patterns. (3) To elucidate the mechanisms by which different shear flow patterns regulate EC proliferation and apoptosis. (4) To establish the mechanisms by which different shear flow patterns regulate EC remodeling, molecular signaling and proliferation/apoptosis in blood vessels ex vivo. (5) To establish the mechanisms by which different shear flow patterns regulate EC remodeling, molecular signaling and proliferation/apoptosis in blood vessels in vivo. Dr. Shu Chien, in cooperation with Drs. Y.C. Fung, Juan Lasheras and Roger Tsien at UCSD, will lead the projects for the studies under all specific aims. Dr. Michael Sheetz at Columbia University will be responsible for identifying the roles of membrane tension and cytoskeleton affinity for cytoplasmic proteins in mechanotransduction. Dr. Jun-Lin Guan at Cornell University will study the molecular mechanisms regulating EC functions, especially in relation to KLF2 and FAK. The interdisciplinary research conducted under this Bioengineering Research Partnership will elucidate the mechanical and molecular bases of the differential adaptive changes of the ECs in response to different flow patterns. The findings obtained from these studies will advance our fundamental knowledge on mechanotransduction and remodeling, thus providing the mechanistic basis for the development of novel approaches for diagnosis and treatment of cardiovascular disorders.
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