The goal of this proposal is to further the understanding of the basic physiological and pathological changes that occur in veins transplanted into the arterial circulation at the tissue, cellular and molecular level. Vein grafting into the arterial circulation results in smooth muscle cell proliferation with the formation of intimal hyperplasia. Of grafts that fail, about 25% do so because of these adverse changes within the graft wall itself. Long-term graft failure is often due to the subsequent development of accelerated atherosclerosis. Adverse changes in endothelial function may be a primary event in the formation of graft intimal hyperplasia and atherosclerosis.
The aims of this proposal are to define the role of the endothelium, the role of platelets and inflammatory cells, and hemodynamic factors in the initiation of vein graft intimal hyperplasia; to examine the mechanism of the self-limitation of intimal hyperplasia and to determine the vasomotor function of intimal hyperplastic and atherosclerotic vasculature as it is related to receptor alterations associated with growth stimulation; and to determine the underlying reasons for the susceptibility of intimal hyperplasia to atherosclerosis. A comprehensive approach using several vein graft models as well as tissue culture systems is proposed in order to achieve these aims. The initiation and progression of intimal hyperplasia will be defined in grafts where severe endothelial injury is likely to occur (reversed vein grafts) , where endothelial injury may not occur (in situ vein grafts) and where there are different hemodynamic factors (a-v fistula, pressure, flow). These vessels will be examined for platelet and other blood cell adherence and infiltration into their walls. The grafts will be assessed for alterations in prostaglandin and matrix synthesis and changes in gene expression. The development of atherosclerosis in vein grafts will also be examined, especially in terms of surface and metabolic alterations in the vessels. The vasomotor function of grafts in hypertensive and atherosclerotic animals will be defined at various stages of lesion formation. This information will be used to develop strategies for the inhibition of intimal hyperplasia by drug therapy. Cultured endothelial and smooth muscle cells will be used to define the aberrations in the metabolic and vasomotor responses of cells derived from normal vasculature and from early and late lesions in grafts.
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