# Effect of Lipids on Vascular Graft Healing > **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $501,719 ## Abstract Project Summary/Abstract Endothelial cell (EC) migration is essential to heal arterial injuries such as those that occur during balloon angioplasty or bypass grafting. Oxidized low-density lipoprotein (oxLDL) and lysophosphatidylcholine (lysoPC), a product of LDL oxidation and the major lysophospholipid in oxLDL, accumulate in atherosclerotic arteries and at sites of arterial injury, and inhibit EC migration. Limited EC healing contributes to thrombogenicity, smooth muscle cell proliferation, and eventual restenosis. Rapid EC healing has been shown to limit intimal hyperpla- sia after angioplasty or prosthetic graft implantation. Lipid oxidation products cause a prolonged rise in intracellular free calcium ion concentration ([Ca2+]i) that inhibits EC migration. We discovered that oxLDL and lysoPC activate canonical transient receptor potential 6 (TRPC6) channels, and this initiates a series of events leading to activation of TRPC5 that is responsible for the prolonged increase in [Ca2+]i that inhibits EC migration. The importance of the TRPC6 to TRPC5 activation cascade in vivo is shown by: 1) the activation of TRPC6 and TRPC5 by a high cholesterol diet, and 2) the inhi- bition of arterial healing in wild-type mice on a high cholesterol diet, but dramatically less inhibition in TRPC6-/- or TRPC5-/- mice. Unfortunately, no TRPC6 inhibitor has been developed for clinical use. We have discovered, however, that TRPC6 activation requires influx of calcium through arachidonic acid-regulated calcium (ARC) channels. Based on our preliminary data, we postulate that lipid oxidation products activate TRPC6 channels by activating phospholipase A2 (PLA2) to release cellular arachidonic acid that opens ARC channels. The Ca2+ that enters through the ARC channels activates a Src kinase that leads to the opening of TRPC6 chan- nels. To test this hypothesis we will determine the mechanism of the initial lysoPC-induced increase in [Ca2+]i, investigating the role of PLA2 activation and ARC channels and the specific type of PLA2 involved. We will also explore the mechanism by which the increase in [Ca2+]i activates TRPC6, investigating the specific Src kinase that is activated. The effect of PLA2 and Src kinase inhibitors on TRPC6 activation and EC migration in vitro will be studied, and the ability of these inhibitors to block TRPC activation and promote EC healing and inhibit intimal hyperplasia will be explored in animals on a chow or high fat diet using a mouse carotid injury model and a rabbit vascular graft model. The proposed studies will lead to a better understanding of the mechanisms by which lipid oxidation prod- ucts inhibit EC migration and promote intimal hyperplasia. This will allow development of targeted interventions to inhibit TRPC6 activation and promote EC migration into angioplasty sites or onto cardiovascular implants to improve the outcome after vascular interventions in patients with cardiovascular disease. ## Key facts - **NIH application ID:** 9838763 - **Project number:** 5R01HL064357-15 - **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU - **Principal Investigator:** Linda M Graham - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $501,719 - **Award type:** 5 - **Project period:** 2000-08-01 → 2021-11-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9838763 ## Citation > US National Institutes of Health, RePORTER application 9838763, Effect of Lipids on Vascular Graft Healing (5R01HL064357-15). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9838763. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*