The goal is to understand the effects of mechanical forces resulting from blood flow and vessel wall strain on the endothelial cells lining the cardiovascular system. State of the art Theological, cell, and molecular biology techniques will be used to study problems which impact directly on atherosclerosis, inflammation, and thrombosis. The overall hypothesis is that expression of atheroprotective versus atherogenic endothelial cell phenotypes depends on the balance of generation and removal of reactive oxygen species, which is strongly modulated by blood flow and wall strain. Endothelial cells will be subjected to steady shear stress, non- reversing pulsatile shear stress (atheroprotective - high mean wall shear stress), and reversing pulsatile shear stress (atherogenic - low mean wall shear stress). The effects of these 3 regimens on endothelial cell gene expression and functional sequelae will be examined in the first specific aim.
In specific aim 2, the functional contribution(s) of cytochromes P4501AT and 1B1, the genes most highly up-regulated under steady shear stress in previous microarray studies will be assessed. We hypothesize that these proteins produce lipid metabolites that are an endothelial-derived hyperpolarizing factor and a PPARgamma- activating ligand, either of which would be atheroprotective.
In specific aim 3, the functional contribution of connective tissue growth factor and cysteine-rich 61 genes, which were strongly down-regulated by shear stress, and their proteins, which have been found in atherosclerotic plaques, will be determined.
The final aim will focus on cyclic strain effects on reactive oxygen species signaling pathways. Vessel wall strain and fluid shear stress impose quite different mechanical loads on endothelial cells and can lead to different effects on gene expression (e.g.endothelin-1 and monocyte chemotactic protein-1). Some vascular regions prone to atherosclerosis have high wall strains, that may mitigate the atheroprotective effect of shear stress. Elucidating how cells in the vessel wall respond to changes in mechanical forces will lead to better strategies for prevention and treatment of cardiovascular diseases, a leading cause of death in the United States, claiming almost 2,600 Americans daily. For 2005, the estimated direct and indirect costs of cardiovascular diseases and stroke in the United States are $393.5 billion.
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