# Metabolic and epigenetic reprogramming in the inflamed endothelium

> **NIH NIH P20** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2024 · $282,611

## Abstract

Endothelial cells (ECs) form a dynamic interface between the blood and underlying tissue. Consistent with 
their specialized functions across vascular beds and the ability to rapidly respond to different 
(patho)physiological stimuli, ECs are both remarkably heterogeneous and highly metabolically active. 
Furthermore, given its strategic location the endothelium plays a key role in inflammation, which underlies 
many human diseases. Recent studies have shown that inflammation-induced EC dysfunction coincides with 
changes in metabolic pathways, particularly enhanced glycolysis. As a result, cells can accumulate metabolic 
intermediates such as acetyl-CoA. In addition to their known roles in metabolism, these metabolites are also 
important in mediating epigenetic processes such as histone acetylation, and thereby regulate cell function. 
While histone modifications are in principle reversible, they can be retained and lead to cellular memory. This 
is not only important for cell type identity, but also plays a role in innate immunity. However, whether 
inflammation-induced metabolic reprogramming in ECs can directly affect epigenetic modifications and cell 
function, and/or lead to cellular memory, is not known. Therefore, this project proposes two specific aims to 
test the hypothesis that inflammation-induced endothelial cell dysfunction is mediated by increased glycolysis 
and histone acetylation, which can subsequently lead to a sustained epigenetic signature. Aim 1 will evaluate 
the in vivo effects of acute inflammation on cellular function in an EC-specific manner using various metabolic 
phenotyping and high-throughput sequencing approaches, both in the absence and presence of a glycolysis 
inhibitor. In addition, targeted spatial transcriptomics will be employed to determine the contribution of distinct 
EC subsets in inflammation-induced endothelial dysfunction. In aim 2 we will perform in vitro assays using 
human ECs to further study the molecular mechanisms underlying metabolic reprogramming and epigenetic 
modifications under inflammatory conditions, and determine whether these modifications can be retained and 
lead to cell memory. The results obtained in this project will provide valuable insights into EC (dys)function, 
and have the potential to identify therapeutic targets for metabolism- and/or epigenetic-centric treatment of 
inflammation-related disorders.

## Key facts

- **NIH application ID:** 10798162
- **Project number:** 5P20GM139763-04
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Audrey Cleuren
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $282,611
- **Award type:** 5
- **Project period:** 2021-02-05 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798162

## Citation

> US National Institutes of Health, RePORTER application 10798162, Metabolic and epigenetic reprogramming in the inflamed endothelium (5P20GM139763-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10798162. Licensed CC0.

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