Effect of Oxidized Lipids on Endothelial Migration and Vascular Graft Healing

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DESCRIPTION (provided by applicant): Prosthetic grafts are used widely in vascular reconstructive surgery, but their long-term patency is limited, in part due to altered cell function caused by oxidized low density lipoprotein (oxLDL). We have shown that: 1) graft material stimulates monocytic cells to oxidize LDL in vitro, 2) this oxLDL inhibits endothelial cell (EC) migration in vitro, 3) explanted grafts contain significantly more lipid oxidation products than the adja- cent aorta, and 4) hypercholesterolemia leads to reduced EC migration onto grafts in rabbits. We also have preliminary data that lysophosphatidylcholine (lysoPC), a lipid oxidation product that accounts for most of oxLDL's inhibitory activity, decreases the level of the nuclear transcription factor peroxisome proliferator- activated receptor y (PPARy), and that PPARy ligands preserve EC migration in lysoPC. Based on these data, we propose as a hypothesis that specific lipid oxidation products that accumulate within synthetic vascular grafts inhibit PPARy allowing continued inflammation and production of reactive oxygen species (ROS) contributing to the inhibition of EC migration, thereby limiting endothelialization of prosthetic grafts in vivo. The goals of this project are to determine the effect of oxLDL and lysoPC on PPAR expression and activity and the effect of PPARs on EC migration in vitro and in vivo. To test our hypothesis, we will determine the effect of oxLDL and lysoPC on PPARa and PPARy expression and activity in EC in vitro and explore mechanisms by which PPAR ligands preserve EC migra- tion in the presence of lipid oxidation products, specifically their effect on lysoPC-induced ROS production. We will investigate the effect of PPARs on graft healing in vivo, comparing PPARa and PPARy expression in ePTFE grafts and normal aorta in rabbits on regular chow and hypercholesterolemic diets, and assess the effect of PPARy ligand on EC ingrowth in ePTFE grafts in these rabbits. The proposed studies will investigate the role of lipid oxidation products in the limited endothelialization of synthetic vascular grafts. Studies will also address the efficacy of PPARy ligands to promote EC healing in vivo. This will lead to a better understanding of the role of lipids in the pathobiology of graft failure, and ultimately, to methods promoting endothelialization of prosthetic grafts and prolonging patency of small- diameter conduits. Lay summary: The goal of our research is to learn more about why bypass grafts fail and ways to prevent it. Specifically, we will study why the cells that normally line blood vessels fail to cover synthetic bypass grafts.