Approximately 30% of vascular interventions using grafts and stents to correct the problems associated with atherosclerosis fail largely as a result of intimal hyperplasia resulting from smooth muscle cell (SMC) growth and wall thickening. While most research has been directed at preventing wall thickening, an alternative might be to stimulate neointimal atrophy after lumenal narrowing has developed. We have demonstrated that high blood flow induces neointimal atrophy in baboon PTFE grafts, but not in the normal iliac artery. We have also found that bone morphogenetic protein (BMP}-4 is induced by high blood flow, while the. BMP inhibitor noggin is suppressed. We propose to test the hypothesis that neointimal atrophy requires a loss of wall tension in the presence of inflammation by comparing loose and tight PTFE wraps around the baboon artery with high blood flow. We will use subtractive suppressive hybridization with DMA microarrays to identify a short list of genes that are regulated during atrophy of both graft neointima and artery and will then determine whether these genes are expressed (or repressed) in the thinning fibrous cap of stenotic atherosclerotic human carotid arteries. We will determine whether baboon neointimal atrophy involves the loss of specific matrix molecules (especially versican) by quantitating glycosaminoglycans using fluorophore assisted carbohydrate electrophoresis. Finally, we will test the hypothesis that an established neointima can be induced pharmacologically to atrophy by overexpressing BMP-4 in the face of normal blood flow. In addition, we will test whether overexpressing noggin blocks high blood flow-mediated neointimal atrophy.
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