Hemodynamic forces regulate the structure and function of the blood vessel wall. Vascular endothelial cells (ECs) are exposed to shear stress, the tangential component of the hemodynamic forces acting on the vessel wall. ECs in the straight part of the arterial tree are subjected to laminar flow with high shear stress, whereas cells in the bends and bifurcations are under disturbed patterns with low shear stress but high shear stress gradient. Our hypothesis is that the preferential localization of atherosclerosis in the branch points of the arterial tree and the sparing of the straight parts can be related to the different molecular responses to these flow patterns. The laminar flow in the straight part of the vessels is anti-atherogenic by arresting the EC cell cycle. In contrast, disturbed flow at branch points is pro-atherogenic by increasing EC proliferation. Laminar flow enhances the repair of the dysfunctional endothelium by augmenting EC migration, in comparison to disturbed flow. We will test our hypothesis that laminar flow and disturbed flow activate different molecular signaling pathways to result in the expression of unique sets of genes, thus leading to the functional consequences of anti-atherosclerosis and pro- atherosclerosis, respectively. The research design has three Specific Aims.
In Specific Aim 1, we will establish the molecular basis of the regulation of EC cell cycle by different flow patterns.
In Specific Aim 2, we will elucidate the molecular mechanisms by which EC migration is modulated by laminar and disturbed flows.
In Specific Aim 3, we will identify the genes regulated by laminar flow and disturbed flow by using DNA microarray technology, with the aim of guiding in-depth studies on the flow-responsive genes that modulate EC cell cycle and migration. The proposed research involves partnership among scientists with expertise in vascular biology, physiology, biomechanics, bioengineering, bioinformatics, cell biology, and molecular biology. This interdisciplinary research program will allow us to elucidate the molecular basis of flow-induced modulation of EC turnover and migration, which are two important processes for vascular remodeling. The results from this BRP application will serve to generate new knowledge on mechano- transduction and vascular biology, provide new understanding of the molecular and biomechanical bases of pathogenesis of vascular disorders such as atherosclerosis, and help to develop new therapeutic strategies.
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