The long-term goal of our research is to improve patency of prosthetic vascular grafts by controlling intimal hyperplasia. Intimal hyperplasia is characterized by smooth muscle cell (SMC) accumulation and matrix deposition, and is most severe adjacent to the anastomoses of prosthetic grafts. The cause of anastomotic intimal hyperplasia is not known. We propose that oxidatively-modified lipids and lipoproteins play a role in vascular graft failure since lipid oxidation products accumulate in prosthetic grafts, and oxidized low density lipoprotein (oxLDL) possesses a number of properties which would adversely affect graft healing, including stimulation of SMC proliferation and extracellular matrix production. Our preliminary studies document lipid oxidation products in prosthetic grafts, high levels of PDGF and collagen production by SMC cultured from prosthetic grafts compared to aortic SMC, and the ability of oxLDL to stimulate PDGF production by graft but not aortic SMC. Based on these findings, we propose that oxLDL induces multiple pathologic processes, including stimulation of PDGF production by graft SMC which in turn stimulates collagen production. These alterations in cellular function may result in the development of anastomotic intimal hyperplasia, and eventual failure of synthetic vascular grafts. We will test this hypothesis by studying the effect of oxLDL on PDGF production and collagen synthesis by aortic and graft SMC in vitro. The characteristics of oxLDL-stimulated PDGF production by aortic and graft SMC will be compared. The mechanism by which oxLDL exerts its effect, including the role of reactive oxygen species, will be addressed. Next, the effect of PDGF on collagen production by SMC will be investigated. Finally, the effect of oxLDL on collagen production by aortic and graft SMC will be studied. The mechanism by which oxLDL stimulates SMC collagen production, including the role of growth factors and reactive oxygen species will be assessed. Both SMC accumulation and extracellular matrix production are critical in the development of intimal hyperplasia. The proposed studies will lead to a better understanding of the role of lipids and SMC in the pathophysiology of graft failure. This will set the stage for future in vivo studies on the efficacy of therapies, such as dietary antioxidants, to control lipid oxidation and promote graft healing. Ultimately, this may lead to treatments which will inhibit the development of anastomotic intimal hyperplasia.
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