# Chloride channels in diabetic vascular disease

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2022 · $380,000

## Abstract

PROJECT SUMMARY/ABSTRACT:
 Diabetes affects ~23 million people in the US alone with the most prevalent form of the
disease being type-2 diabetes (T2D), which accounts for ~90%, of diagnosed cases. Obesity,
physical inactivity coupled with genetic susceptibility is associated with the rising prevalence of
T2D. The risk of cardiovascular disease (CVD) increases 3-fold in diabetes and involves several
factors, including hyperglycemia, insulin resistance and dyslipidemia. Peripheral artery disease
(PAD) commonly occurs in diabetes and manifests as occlusive arterial disease of the lower
extremities. PAD generally points to poor prognosis because it is indicative of wider CVD risk
especially involving the cerebrovascular, coronary and renovascular systems.
 Vascular smooth muscle cell (myocyte) membrane potential is a major regulator of
arterial contractility. Diabetes can alter the expression and activity of several ion channels in the
vasculature that are associated with intracellular calcium (Ca2+) signaling. Transmembrane
protein 16A (TMEM16A, Anoctamin1, ANO1) channels are Ca2+-activated chloride (Cl−)
channels that are expressed in arterial myocytes and triggers Cl- efflux, myocyte membrane
depolarization and vasoconstriction. Arterial myocyte ion channel gene expression is tightly
regulated by signaling mechanisms mediated by several transcription factors. A pathological
alteration in these regulatory mechanisms may affect channel expression and induce vascular
dysfunction in diabetes. The role of arterial myocyte ANO1 in the development of diabetic
vascular dysfunction has not been investigated. This application stems from novel and exciting
data of specific signaling mechanisms that regulate Ano1 expression in arterial myocytes to
control arterial contractility. Diabetes-induced dysregulation of these signaling pathways leads to
increased arterial myocyte ANO1 expression, ANO1 currents and vasoconstriction. The goal of
this proposal is to identify key proteins and signaling mechanisms mediating Ano1 expression in
resistance arteries and test the therapeutic potential of novel compounds in alleviating diabetes-
induced vasoconstriction.

## Key facts

- **NIH application ID:** 10306352
- **Project number:** 5R01HL149662-03
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** M. Dennis Marcus Leo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $380,000
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10306352

## Citation

> US National Institutes of Health, RePORTER application 10306352, Chloride channels in diabetic vascular disease (5R01HL149662-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10306352. Licensed CC0.

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