# Endothelial Metabolism and Redox Imbalance in Vascular Disease

> **NIH NIH P01** · AUGUSTA UNIVERSITY · 2024 · $2,264,097

## Abstract

PROJECT SUMMARY
Redox imbalance between reactive oxygen species (ROS) and reactive nitrogen species (RNS) (high ROS and
low nitric oxide NO) is a fundamental mechanism of endothelial cell (EC) dysfunction and a driver of
cardiovascular diseases (CVD) such as atherosclerosis, hypertension and peripheral arterial disease (PAD).
Strategies to individually mitigate ROS or amplify NO have experienced limited success. Therefore, a greater
understanding of the key factors and events that lead to redox imbalance is therefore essential to develop more
effective treatments for cardiovascular disease (classical concept) which remains the leading cause of morbidity
and mortality. In ECs, aerobic glycolysis (“Warburg effect”) has been regarded as the dominant metabolic
pathway supporting homeostatic functions. An emerging concept is that the pathways of cellular metabolism are
not fixed, and that ECs can alter their metabolic pathways or “reprogram” to meet different needs. A major gap
in our knowledge is how EC metabolism and ROS/RNS balance are altered in vascular disease and how
metabolism informs function. Recent studies have shown that aerobic glycolysis is increased in ECs of
atherosclerotic, diabetic and angiogenic blood vessels, however, the functional consequences of this dynamic
has yet to be elucidated. Enzymes that produce ROS are not only influenced by metabolism, but may also
promote changes in metabolism. Our preliminary data advance the novel hypothesis that imbalance between
changes in EC metabolism and ROS/RNS (redox balance), induced by various risk factors, is a key driver
of EC dysfunction and an underlying mechanism of vascular disease. To test this hypothesis, a
programmatic approach is essential as it is the only mechanism capable of supporting the rigor needed to
investigate the complex interplay between metabolism and redox signaling in different vascular beds and disease
states. Our program has 3 well aligned projects that benefit from the synergy of model and reagent sharing and
dedicated cores. Project 1 is focused on the hypothesis that disturbed copper (Cu) metabolism in ECs arises
from dysfunction of the Cu exporter, ATP7A, leading to excessive PFKFB3/glycolysis, ROS/NO imbalance and
mitochondrial ROS-epigenetic remodeling that drives EndMT and accelerated atherosclerosis. Project 2 will test
the hypothesis that EC metabolism shapes EC function via sex-specific, Nox1 and leptin-dependent mechanisms.
Project 3 tests the hypothesis that ability of the mitochondrial dynamics protein, Drp1, to promote reparative
angiogenesis via crosstalk between EC mitochondrial redox signaling and glycolysis is impaired in diabetes due
to excess PFKFB3/glycolysis-ROS signaling which increases the severity of PAD. To test these concepts directly,
we have developed a state-of-the-art approach using CRISPR/Cas9 to generate knock-in mice enabling
inducible reduction of glycolysis only in ECs, that will be shared across projects to enhance synergy.
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## Key facts

- **NIH application ID:** 10847543
- **Project number:** 1P01HL160557-01A1
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** TOHRU FUKAI
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,264,097
- **Award type:** 1
- **Project period:** 2024-06-05 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10847543

## Citation

> US National Institutes of Health, RePORTER application 10847543, Endothelial Metabolism and Redox Imbalance in Vascular Disease (1P01HL160557-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10847543. Licensed CC0.

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