# Repair of Vascular Contractility and Mitochondrial Function by NOS Recoupling

> **NIH VA IK2** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2021 · —

## Abstract

Diabetes (DM) is prevalent in the Veteran community, and there is an excess risk of cardiovascular disease
(CVD) in those suffering from this disease. Early signs of CVD pathology include disruptions in vascular cells,
making the vasculature a prime target for novel therapeutics. Hormesis, or the ability of cells to adapt and self-
regulate when exposed to stress, is disrupted in the vasculature of those with DM. A central lynchpin of
homeostasis modulation is the enzyme nitric oxide synthase (NOS). NOS regulates vascular contractility
through the production of nitric oxide (NO) and also modulates mitochondrial function. We have shown that
the impaired vascular function in animal models of DM is correlated to NOS dysfunction and altered
mitochondrial substrate metabolism, function, and dynamics. It is unknown whether restoration of
mitochondrial substrate metabolism would repair NOS activity, cellular and mitochondrial function, redox
processes, and/or vascular function in those with DM. We hypothesize that disrupted cellular homeostasis
intrinsic to the DM vasculature can be restored by reestablishing physiological NOS regulation and
mitochondrial fuel metabolism. Many bioactive plant compounds are a platform for commonly used
pharmaceuticals and have myriad physiological effects. The flavonoid compound -(-) epicatechin has been
shown to induce vasodilation through the direct modulation of NOS; in previous studies, this compound also
attenuated excess ROS and improved mitochondrial function. To test our hypothesis, we will treat animal
models of DM with the plant compound -(-) epicatechin and measure NOS activity, mitochondrial function and
substrate utilization, and vascular contractility. In vitro experiments in endothelial cells treated with -(-)
epicatechin will determine the upstream cellular regulation of our functional endpoints. Secondly, we will test
the cellular regulation of antioxidant defense in endothelial cells treated with -(-) epicatechin and ascertain any
effects on cellular signaling pathways. Ultimately, we will investigate whether the cells' innate homeostatic
regulation will be restored by repairing NOS activity with this plant compound. As this natural product is
available in food and as a supplement, it may be a candidate for immediate therapeutic use for Veterans
suffering from DM and CVD.

## Key facts

- **NIH application ID:** 10266011
- **Project number:** 5IK2BX003185-05
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** Amy Celeste Keller
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10266011

## Citation

> US National Institutes of Health, RePORTER application 10266011, Repair of Vascular Contractility and Mitochondrial Function by NOS Recoupling (5IK2BX003185-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10266011. Licensed CC0.

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