# Enhancing parasympathetic activity to reduce vascular oxidative stress and endothelial dysfunction

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $759,509

## Abstract

Project Summary
Endothelial dysfunction, a pro-thrombotic, inflammatory condition that causes impaired vascular reactivity is an
early reversible step in the development of atherosclerosis and cardiovascular disease (CVD). Multiple studies
consistently shown that African Americans (AAs) have impaired endothelial function compared to whites.
African Americans also experience disproportionately higher CV morbidity and 20% higher mortality than
whites or Hispanics. Endothelial dysfunction is caused by the overproduction of reactive oxygen species
(ROS), particularly superoxide which interferes with endothelial-derived nitric oxide signaling pathways. One of
the major sources of superoxide is NADPH oxidase; our previous work found that activation of NADPH oxidase
contributes to vascular oxidation through the formation of highly immunogenic isolevuglandins (IsoLG-protein
adducts) in peripheral mononuclear cells (PBMCs), which stimulates antigen presenting cells (APC) and
inflammatory mediators. Inflammation and oxidative stress are modulated by the parasympathetic nervous
system (PNS). We and others found that AAs have reduced PNS activity compared with whites. Our
preliminary data in obese AA women found that stimulation of the PNS cholinergic transmission with the
acetylcholinesterase inhibitor, galantamine, blocked the production of oxidative stress and inflammatory
cytokines induced by lipids. The overall goal of the current proposal is to determine if prolonged treatment with
galantamine improves endothelial dysfunction and vascular oxidative stress in AAs. For this purpose, we will
conduct a proof-of-concept, blinded, randomized, placebo-controlled study to test the effect of 3-month
treatment with galantamine (16 mg/day) on vascular oxidative stress and impaired vascular reactivity in AAs.
 Specifically, we will evaluate whether galantamine treatment inhibits the activation of NADPH-IsoLG formation
and the subsequent immunogenic responses in PBMCs. Furthermore, we will determine if galantamine
decreases markers of oxidative stress and inflammation in harvested endothelial cells (ECs) and improves
vascular reactivity in the same study subjects. The planned studies will provide a comprehensive assessment
of the mechanism underlying the effect of increased PNS cholinergic transmission on endothelial dysfunction.
If our hypothesis is correct, and galantamine improves endothelial dysfunction in AAs, a population with a high
risk for CVD, we will discover a novel mechanism that could alter the oxidative and immunogenic responses in
this population and will offer a potential pathway for the development of more effective therapies aimed at
decreasing CVD.

## Key facts

- **NIH application ID:** 10418658
- **Project number:** 5R01HL157584-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Annet Kirabo Kirabo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $759,509
- **Award type:** 5
- **Project period:** 2021-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10418658

## Citation

> US National Institutes of Health, RePORTER application 10418658, Enhancing parasympathetic activity to reduce vascular oxidative stress and endothelial dysfunction (5R01HL157584-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10418658. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*