Atherosclerosis is a disease effecting millions of people each year with significant morbidity and mortality. A common surgical treatment of this disease is bypass grafting, using autogenous vein conduit. The longevity of these bypass grafts, however, is limited by the development of intimal hyperplasia (IH) which ultimately leads to graft failure. Certain growth promoters found in the smooth muscle cells of a hyperplastic vessel wall include platelet derived growth factor (PDGF) and transforming growth factor - beta (TGF-Beta) both of which are important contributors to the dynamic process of IH. In addition, an extracellular matrix is formed within these vessels consisting of collagen types I and III. Nitric oxide (NO) has been identified as an important modulator of vascular tone, platelet and white blood cell function and smooth muscle cell proliferation, all key components in the development of IH. As yet all pharmacological strategies aimed at arresting intimal hyperplasia have been unsuccessful. NO donors (NOD) are a class of drugs that release NO under physiologic conditions and therefore, have therapeutic effects.
The aims of this project are to quantitate the IH, endothelial dependent potential and the expression of PDGF-A, TGF-Beta, collagen types I and III, in addition to nitric oxide synthase isoforms iNOS and cNOS in vein grafts in rabbits treated with the NOD, pirsidomine. The purpose of this research proposal is to establish the involvement of nitric oxide in the inhibition of intimal hyperplasia in vein bypass grafts and ultimately to the development of a new pharmacologic intervention to prevent vessel restenosis and graftfailure.
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