The overall objective of this research is to understand the factors affecting the transendothelial entry of macromolecules into the arterial wall, and particularly the mediation of this process by local hemodynamics. The interest in macromolecular transport is prompted by its importance in the genesis and development of artherosclerosis. The mediation of arterial uptake by hemodynamic factors is of particular interest because the distribution of atherosclerotic lesions suggests that hemodynamic factors may be involved in the localization of the disease; furthermore, there is evidence that hemodynamic stress can influence endothelial permeability. A primary hypothesis of this research is that an important fraction of the transendothelial flux occurs during increases in permeability prompted by changes in flow; accordingly, particular emphasis is placed on the dynamic response of the barrier function of the endothelial lining to changes in the hemodynamic environment. The research objectives are addressed through a unique combination of animal experiments, computer simulation and cell and molecular biology. The spatial variation of the albumin permeability in the eternal iliac arteries of swine, either at baseline or subsequent to interventions that alter flow, will be obtained using photographic densitometry of Evans Blue dye to measure albumin uptake. The alterations in flow will be produced by reversible, adjustable femoral arteriovenous shunts. The distribution of wall shear stress, and of the changes in stress caused by manipulating the shunt, in the iliac vessels will be obtained from validated fluid dynamic computations in regions derived from injection casts of the arteries and the proximal vasculature; the dependence of albumin uptake on hemodynamic stress, and alterations in stress, will be assessed and modeled. In a separate set of animals, casting material will not be injected, and tissue from the region of interested will be fixed or explanted and cultured, and a variety of techniques will be used to relate the variations in permeability to cellular properties. Of particular interest are properties that mediate the redox state of the cell, the integrity of the cytoskeleton, and its junctions with neighboring cells and adhesion to the substratum. The effects of hypercholesterolemia on vascular permeability and its dynamic response to changes in flow will be examined as well, to determine whether high lipid levels potential the effects of flow changes on vascular uptake.
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