Linda M. Graham, M.D.
Lerner Research Institute,
9500 Euclid Avenue, Cleveland, Ohio 44195
Phone: (216) 445-3298
Fax: (216) 444-9198
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 cell 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 coronary 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.
Rosenbaum MA, Miyazaki K, Graham LM. Hypercholesterolemia and oxidative stress inhibit endothelial healing after arterial injury. J Vasc Surg 55:489-496. 2012. PMCID: PMC3264759
Rosenbaum MA, Chaudhuri P, Abelson B, Cross BN, Graham LM. Apolipoprotein A-I mimetic peptide reverses impaired arterial healing after injury by reducing oxidative stress. Atherosclerosis. 241:709-715, 2015, PMCID: PMC4529116
Rosenbaum MA, Chaudhuri P, Graham LM. Hypercholesterolemia inhibits reendothelialization of arterial injuries through TRPC channel activation. J Vasc Surg 62(4): 1040-1047, 2015. PMCID: PMC4226809
King AP, Abelson JL, Gholami B, Upchurch G, Henke P, Graham L, Liberzon I. Pre-surgical psychological and neuroendocrine predictors of psychiatric morbidity following major vascular surgery: a prospective longitudinal study. Psychosomatic Medicine. 77(9) 993-1005, 2015. PMCID: PMC4643324
Chaudhuri P, Sinharoy P, Damron DS, Birnbaumer L, Graham LM. Membrane Translocation of TRPC6 Channels and Endothelial Migration are Regulated by Calmodulin and PI3 Kinase Activation. Proc Natl Acad Sci USA 113(8): 2110-2115, 2016. PMCID: PMC4776520
Chaudhuri P, Rosenbaum MA, Birnbaumer L, Graham LM. Integration of TRPC6 and NADPH oxidase activation in lysophosphatidylcholine-induced TRPC5 externalization. Am J Physiol Cell Physiol 313(5):C541-C555, 2017. PMCID: PMC5792165
Shi R, Hu M, Zhang Y, Gao S, Smith AH, Ye J, Cai L, Graham LM, Li C. Ascorbate inducible N259 glycans on prolyl 4-hydoxylase subunit a1 promote hydroxylation and secretion of Type I collagen. Cell Mol Life Sci 76(17): 3449-3464, 2019. PMCID: PMC6698205
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.
Possible Target Identified to Prevent Recurrent Blood Vessel Blockages Following Vascular Procedures
Researchers from the Department of Biomedical Engineering, led by Linda Graham, MD, have identified that a specific gene, TRPC6, plays a role in preventing arteries from narrowing following injury. The team’s findings, published in the Journal of Vascular Science, suggest that targeting TRPC6 and/or related signaling pathways may be a viable new approach to promote normal healing after arterial damage due to angioplasty or other endovascular procedures.