Synthetic grafts used for vascular bypasses have limited long-term patency. Inadequate endothelial cell ingrowth contributes to their long-term thrombogenicity, and smooth muscle cell accumulation with matrix deposition can progress to intimal hyperplasia and graft failure. Oxidized lipids accumulate in prosthetic grafts and contribute to cellular dysfunction. Oxidized lipids inhibit endothelial cell migration in vitro by increasing reactive oxygen species production, altering cell membrane fluidity, disrupting cytoskeletal components, and opening calcium channels. Oxidized lipids also contribute to smooth muscle cells dysfunction on prosthetic grafts. The graft smooth muscle cells acquire a synthetic, proliferative phenotype, and compared with aortic smooth muscle cells, produce higher levels of growth factors and collagen. Oxidized lipids stimulate growth factor and collagen secretion, regulating their production at transcriptional and post-transcriptional levels. Our research is exploring the pathways involved. A better understanding of the changes in cell function on prosthetic grafts, and the mechanisms responsible, will allow development of mechanism-based therapies to improve graft patency.
The long-term goal of our research is improve the healing of bypass grafts or arteries after balloon angioplasty and stenting. We are investigating how oxidized lipids contribute to the build-up of scar tissue and block the movement of endothelial cells (cells that normally line blood vessels) into an area of injury or onto a bypass graft. The results of these studies guide our development of treatments to promote endothelial cell healing and limit scar production after vascular interventions.
Chaudhuri P, Colles SM, Fox PL, Graham LM: Protein kinase Cδ-dependent phosphorylation of syndecan-4 regulates cell migration. Circ Res 97:674-681, 2005.
Miyazaki K, Colles SM, Graham LM: Impaired graft healing due to hypercholesterolemia is prevented by dietary supplementation with α-tocopherol. J Vasc Surg 48:986-993, 2008.
Chaudhuri P, Colles SM, Bhat M, Van Wagoner DR, Birnbaumer L, Graham LM: Elucidation of a TRPC6-TRPC5 channel cascade that restricts endothelial cell movement. Mol Biol Cell 19:3203-3211, 2008.
Rosenbaum MA, Miyazaki K, Colles SM, Graham LM: Antioxidant therapy reverses impaired graft healing in hypercholesterolemic rabbits. J Vasc Surg 51:184-193, 2010.