This proposal seeks to gain an understanding of the pathogenesis of lesions which occur in autologous vein grafts with the aim of suggesting methods by which such lesions may be minimized or prevented. We have developed a reliable nonhuman primate model for studies on themorphological and biochemical changes that take place in veins placed in the arterial circulation. We will use our surgical expertise to develop by microsurgical techniques similar models in the rat and rabbit. We will use the rat and rabbit animal models to help us define the origin of the cells in the intimal thickened vasculature, and in vivo correlation between platelet function and vascular graft-platelet interaction in the initiation of intimal thickening. The inhibition of intimal thickening by in vivo drug treatment will also be examined. We will use the nonhuman primate model for in depth in vitro studies on the metabolic alterations that accompany the initiation of intimal thickening, its apparent self-limitation, and susceptibility to atherosclerotic degeneration.
The aim of these nonhuman primate studies is to define the biological mechanisms responsible for these alterations. To accomplish our goals, we will use organ culture techniques to study the lysosomal activities of normal and intimal thickened vasculature, the ability of these tissues to synthesize connective tissues, and their prostaglandin metabolism. Furthermore, we will use tissue culture techniques for studies of cells derived from the vasculature to determine the mechanism of the cellular proliferation process, and the mechanism of drug effects in this process. We will also investigate in vitro the susceptibility of the vasculature to lipoprotein accumulation and alterations in cellular lipid metabolism.
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