# Endothelial Healing is Inhibited by Activation of TRPC6 Channels

> **NIH VA I01** · LOUIS STOKES CLEVELAND VA MEDICAL CENTER · 2022 · —

## Abstract

Cardiovascular disease is a devastating disorder that has a major impact on length and quality of life.
According to the American Heart Association, approximately 121.5 million Americans carry the diagnosis of
heart disease. Veterans have significantly higher rates of cardiovascular disease starting at younger ages and
have 42% higher odds of having more cardiovascular diseases compared to non-veterans. Higher rates of
cardiovascular disease in veterans with a higher likelihood of cardiovascular morbidity at a younger age leads
to early onset cardiovascular mortality later in life. The number of heart and vascular procedures (balloon
angioplasties and vascular grafts) that will be performed in 2040 is expected to be more than twice the number
performed in 2008 and restenosis requiring reintervention occurs in 30-75% of procedures depending on the
treatment area. Similar increases in number of vascular procedures performed and similar restenosis rates
occur in the veteran population.
 When a blood vessel is treated with angioplasty, the endothelial cells (EC) are removed. The cells must
migrate from the edge of the injury into the area of injury to heal it. If healing is delayed, the chance of
restenosis is increased. Lipid oxidation products accumulate in atherosclerotic arteries and at regions of injury,
cause cellular dysfunction, and inhibit EC migration in vitro and in vivo. Limited re-endothelialization contributes
to thrombogenicity, smooth muscle cell proliferation, and restenosis.
 Oxidized lipids cause an inappropriate increase in intracellular free calcium ion concentration ([Ca2+]i)
through canonical transient receptor potential (TRPC) channels, specifically TRPC6. Activation of TRPC6 by
causes an increase in [Ca2+]i that results in activation of TRPC5 and a prolonged increase in [Ca2+]i. The
increased [Ca2+]i activates calpains that break down cytoskeletal proteins inhibiting EC migration. Studies in
TRPC6-/- mice provide compelling evidence of the importance of this cascade in vivo. Re-endothelialization of
injured carotid arteries is dramatically reduced in wild-type (WT) mice on a high fat diet compared with chow-
fed mice, but in TRPC6-/- mice, hypercholesterolemia does not inhibit re-endothelialization of the injury.
 Considerable effort has been directed at identifying a specific TRPC6 inhibitor without success. Non-
selective TRPC inhibitors have developed, but they impact TRPC3, TRPC6, and TRPC7 channels. We have
discovered that lipid oxidation products induce TRPC6 externalization by activating phosphatidylinositol 3-
kinase (PI3K), which generates phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 is anchored in the cell
membrane and promotes TRPC6 translocation to the cell membrane and leads to increased [Ca2+]i. Based on
our ongoing studies, the interaction between PIP3 and TRPC6 is mediated by an adaptor protein, and
preliminary data suggest that this is Grb2-associated binding protein 1 (Gab1). Importantly, identifi...

## Key facts

- **NIH application ID:** 10369226
- **Project number:** 1I01BX005823-01
- **Recipient organization:** LOUIS STOKES CLEVELAND VA MEDICAL CENTER
- **Principal Investigator:** Michael Aaric Rosenbaum
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10369226

## Citation

> US National Institutes of Health, RePORTER application 10369226, Endothelial Healing is Inhibited by Activation of TRPC6 Channels (1I01BX005823-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10369226. Licensed CC0.

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