The focus of much research on intimal hyperplasia and remodeling after arterial injury has been on the prevention of smooth muscle cell growth and wall thickening. However the investigators have made observations in previous work that an alternative strategy might be to stimulate atrophy of the neointima after luminal narrowing has developed. They propose to test the hypothesis that neointimal hyperplasia not only can be inhibited, but it can also be induced pharmacologically to atrophy after it has developed. This hypothesis is based on demonstration that neointimal atrophy occurs in baboon PTFE grafts after a switch from normal to high blood flow, a process linked to the loss of smooth muscle cells and the associated matrix. Preliminary studies showed a marked increase in ecNOS and a decrease in PDGF-A chain expression. The objectives of the current application are to define the mechanisms of neointimal atrophy in PTFE grafts induced by high blood flow and to attempt to induce by pharmacological means neointimal atrophy in the face of normal blood flow by blocking PDGF receptors and by over-expressing ecNOS. The investigators propose a combined in vitro and in vivo approach using cultured baboon and human endothelium and SMCs, a baboon model of graft intimal hyperplasia, and molecular array technology to characterize genes induced or suppressed by changes in blood flow.
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