Prosthetic grafts are used widely in vascular reconstructive surgery, but their long-term patency is limited, perhaps due to altered cell function caused by oxidized low density lipoprotein (oxLDL). In preliminary studies they have shown that: 1) graft material stimulates monocytic cells to oxidize LDL in vitro, 2) this oxLDL inhibits endothelial cell (EC) migration in vivo. This contributes to the prolonged thrombogenicity and eventual failure of these grafts. The goal of this project is to determine the effect of lipids, especially oxidized lipids, on EC migration on prosthetic grafts. To test their hypothesis, the effect of oxidized lipids on EC migration and the mechanism by which oxLDL inhibits EC migration will be studied. The investigators will first investigate the role of reactive oxygen species (ROS) in oxLDL's inhibition of EC migration. They will characterize the effect of oxLDL on superoxide production by EC, assessing the effect of ROS on EC migration, and determining the ability of antioxidants to restore EC migration in the presence of oxLDL. Since ROS alter membrane fluidity and changes in fluidity affect migration, they will investigate the effect of oxLDL on EC membrane fluidity. They will also evaluate the ability of vitamin E and other antioxidants to prevent changes in membrane fluidity and preserve EC migration. The effect of oxLDL on EC migration on ePTFE graft material in vitro will be studied, and the ability of vitamin E or superoxide dismutase to restore migration determined. Finally, they will study the effect of hypercholesterolemia on EC ingrowth onto prosthetic grafts implanted in rabbits, and assess the ability of vitamin E to preserve endothelial migration. The proposed studies will investigate the role of lipids and lipoproteins, and their oxidatively modified derivatives, in the failure of synthetic vascular grafts to endothelialize. Studies will also address the efficacy of treatment with dietary antioxidants to control lipid oxidation and promote graft healing. This will lead to a better understanding of the role of lipids in the pathophysiology of graft failure. Ultimately, this may lead to methods to promote endothelialization of prosthetic grafts and prolong patency of small-diameter vascular grafts.
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