# Arterial Cell Reprogramming by Disturbed Flow and Hypercholesterolemia

> **NIH NIH F31** · EMORY UNIVERSITY · 2024 · $48,974

## Abstract

Project Summary/Abstract
Atherosclerosis is a chronic inflammatory disease characterized by buildup of plaques in the arteries. It is the
major underlying cause of myocardial infarction, ischemic stroke, and peripheral arterial disease, all of which are
leading causes of death worldwide. Despite the prevalent use of statins that lower blood cholesterol levels,
atherosclerosis remains the leading cause of death globally. Therefore, there is a crucial need to develop
therapies that target non-lipid targets for atherosclerosis. Although its risk factors are systemic, atherosclerosis
preferentially develops in arterial regions exposed to disturbed blood flow (d-flow), while those exposed to stable
blood flow (s-flow) are protected. Using the mouse partial carotid ligation (PCL) model of atherosclerosis, the Jo
Lab demonstrated that d-flow can induce atherosclerosis in the presence of hypercholesterolemia, but not with
either alone. Even though these animal studies have shown the importance of d-flow on endothelial dyfucntion
and consequently atherosclerosis development, the mechanisms underlying its development remain to be
studied. To address this crucial gap in knowledge, the Jo Lab’s recent single-cell RNA-sequencing (scRNA-seq)
and single-cell assay for transposase-accessible chromatin-seq (scATAC-seq) studies have revealed that
chronic exposure to d-flow causes Flow-Induced Reprogramming of Endothelial cells (ECs) (FIRE), including
endothelial inflammation, endothelial-to-mesenchymal transition (EndMT), and the novel concept of endothelial-
to-immune cell transition (EndIT) partially. Although d-flow alone could induce significant changes in the EC
genes and FIRE, it requires additional risk factors such as hypercholesterolemia to induce atherosclerosis in
mice. Therefore, it is hypothesized that a combination of d-flow and hypercholesterolemic induces complete
endothelial reprogramming (FIRE), including full EndIT, leading to plaque development. To test this hypothesis,
an scRNA-seq study on the murine PCL model of atherosclerosis was recently performed to compare the effects
of d-flow alone, hypercholesterolemia alone, and d-flow + hypercholesterolemia. As expected, atherosclerotic
plaques developed only under d-flow + hypercholesterolemia in mice. Preliminary scRNA-seq data analysis
shows that ECs appear to undergo not only complete EndIT but also transition to foam cells, endothelial-to-foam
cell transition (EndFT). To accomplish the goal of better understanding the flow-induced mechanisms of
atherosclerosis pathophysiology for development of novel therapies, the following three aims are proposed for
this F31 application: 1) Define arterial cell reprogramming, especially FIRE, that occurs during atherogenesis, 2)
Validate FIRE in mouse and human arteries, and 3) Screen d-flow-sensitive genes of FIRE as potential novel
therapeutic targets for atherosclerosis. Addressing these aims will provide novel insights into the mechanism of
flow-induced...

## Key facts

- **NIH application ID:** 10998460
- **Project number:** 1F31HL176148-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Christian Park
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-09-30 → 2026-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998460

## Citation

> US National Institutes of Health, RePORTER application 10998460, Arterial Cell Reprogramming by Disturbed Flow and Hypercholesterolemia (1F31HL176148-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10998460. Licensed CC0.

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