# Role of Shear-Sensitive Protein HEG1 in Endothelial Biology and Atherosclerosis

> **NIH NIH F31** · EMORY UNIVERSITY · 2022 · $24,788

## Abstract

Project Summary/Abstract
Atherosclerosis refers to the formation of fatty plaques in the arterial wall that underlie heart attacks and
strokes, two of the deadliest medical events in the US and abroad. In general, two criteria must be met in order
to develop atherosclerosis in a given artery: 1) the artery must be exposed to high levels of circulating
cholesterol and lipids, and 2) the artery must typically be located in a curved or branching region of the
vasculature, in which endothelial cells of the arterial wall experience low-magnitude and oscillatory shear
stress from disturbed blood flow. Despite the widespread use of many different cholesterol- and lipid-lowering
medications in the prevention of atherosclerosis, heart attacks and strokes have remained two of the top killers
in the US. As such, it has become increasingly important to develop drugs that target different mechanisms of
atherogenesis, like endothelial responses to disturbed blood flow. The current study addresses this problem by
investigating the role of the flow-sensitive protein heart of glass homolog 1 (HEG1) in endothelial function and
atherosclerosis. HEG1 is an endothelial-enriched single-pass transmembrane glycoprotein that has been
shown to be essential for vascular development and integrity. Recently, our laboratory found that HEG1 is
downregulated in endothelial cells exposed to disturbed flow and upregulated in endothelial cells exposed to
stable flow. This result was confirmed at both the RNA and protein level, in vitro and in vivo, in both human and
mouse endothelial cells. A recent publication demonstrated a similar result in zebrafish. Due to the clear shear-
sensitivity of HEG1 and its demonstrated importance in vascular development and integrity, we hypothesize
that downregulation of HEG1 in response to disturbed flow causes endothelial dysfunction, which contributes
to the development of atherosclerosis. To test this hypothesis, we propose two aims: 1) to determine the role of
HEG1 in endothelial dysfunction, and 2) to determine the role of HEG1 in the pathogenesis of atherosclerosis.
To address Aim 1, HEG1 will be overexpressed and knocked down in human aortic endothelial cells, and these
cells will be assessed in a series of experiments testing common endothelial functions such as permeability,
inflammation, and migration. Mechanistic studies will subsequently be performed in order to describe exactly
how HEG1 is involved in endothelial function. To address Aim 2, HEG1 will be knocked down in mice, and
these mice will be subjected to our partial carotid ligation, flow-induced atherosclerosis model. Markers of
endothelial dysfunction and atherosclerosis will be studied in these mice in order to assess the effects of
endothelial HEG1 expression on disease pathogenesis. Addressing these aims will shed light on the effects of
HEG1 downregulation in endothelial cells exposed to disturbed flow and provide a novel mechanism to target
in the treatment of atheroscle...

## Key facts

- **NIH application ID:** 10473801
- **Project number:** 5F31HL149285-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Ian A. Tamargo
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $24,788
- **Award type:** 5
- **Project period:** 2020-07-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10473801

## Citation

> US National Institutes of Health, RePORTER application 10473801, Role of Shear-Sensitive Protein HEG1 in Endothelial Biology and Atherosclerosis (5F31HL149285-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10473801. Licensed CC0.

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