The long range objective of my research efforts is to provide a better understanding of the role of the vascular endothelium and lipoproteins in the genesis of atherosclerosis. The specific focus of my current work is to determine the mechanism of vascular hyperpermeability that occurs during atherogenesis. Heightened endothelial permeability is an important factor for atherosclerotic plaque development. This hyperpermeable state is likely the consequence of endothelial dysfunction. Likewise, lipoproteins, especially elevated low density lipoprotein (LDL) concentrations, have been demonstrated through epidemiologic studies to be associated with the premature development of atherosclerosis. One mechanism whereby vascular hyperpermeability could occur in the presence of an intact endothelium is increased endocytotic transport. I have demonstrated, in vitro, increased endothelial endocytotic activity with prolonged exposure to atherogenic LDL levels. Findings suggest that cytoskeletal remodeling with stress fiber formation is involved in the mechanism of this cellular functional change. The goal of the present proposal is to provide further information on the physiologic mechanism(s) for"""""""" lipoprotein-mediated alterations in endothelial endocytosis. A major aspect of these studies will be to examine the contributions of arachidonic acid metabolites, calcium fluxes, and adenosine metabolites. These studies will be carried out in vitro employing a tissue culture system consisting of human vascular endothelial cells exposed to high lipoprotein concentrations for prolonged periods. The lipoproteins to be examined include LDL, very low density lipoprotein, and high density lipoprotein. Results from these studies should provide new insights into important physiologic mechanisms for lipoprotein-induced hyperpermeability.
