# Mechanisms Underlying Sympathetic Activation-dependent Endothelial Cell Activation by Chronic Intermittent Hypoxia

> **NIH NIH P01** · UNIVERSITY OF CHICAGO · 2022 · $380,700

## Abstract

Project Summary- Project 3
Patients with sleep apnea (SA) and rodents exposed to intermittent hypoxia (IH), a hallmark of SA, exhibit
endothelial cell (EC) activation, which is an early pathologic event in the development of cardiovascular
disease. When activated, ECs express increased levels of pro-inflammatory cytokines and cell adhesion
molecules leading to leukocyte adhesion to EC. The overall goal of Project 3 is to determine the mechanisms
underlying EC activation caused by SA/IH. Our preliminary data from IH-exposed mice and aortic ECs suggest
that SA/IH-induced EC activation is not caused directly by IH but secondarily by IH-induced sympathetic
activation-derived epinephrine (not by norepinephrine). Furthermore, we found that treating ECs with
epinephrine activates hypoxia-inducible factor (HIF)-1, and increases glycolysis, both of which we recently
found to be required for EC activation under abnormal blood flow. Based on the preliminary data, Project 3 will
test the hypothesis that SA/IH causes EC activation indirectly via sympathetic activation-derived epinephrine,
which through β2-adrenergic receptors activates HIF-1α leading to upregulation of glycolysis, which is required
for EC activation. We will test our hypothesis in three specific aims in two models of SA/IH: (1) experimental
exposure of IH and (2) mice with spontaneous SA. In Aim 1, we will determine whether sympathetic activation-
derived epinephrine mediates IH-induced EC activation and macrophage adhesion. In Aim 2, we will determine
whether β2-adrenergic receptors are required for IH-induced EC activation. In Aim 3, we will determine whether
IH-induced epinephrine causes EC activation through HIF-1-dependent manner and further assess the
mechanism(s) by which HIF-1 is activated by IH-induced epinephrine. In Aim 4, we will determine whether
increased glycolysis by HIF-1 is required for IH-induced EC activation. Project 3 has tight thematic linkages to
Projects 1, 2, and 4 and utilizes Core B facilities for: a) exposing mice to IH, b) maintenance and genotyping of
genetically engineered mice; c) quantitative real-time-PCR analysis. Members of the investigative team have
long-standing experience and expertise with the proposed approaches and excellent track record of working
together for number of years as evidenced by joint publications. The proposed studies will provide a framework
for understanding the specific role of CIH-induced sympathetic activation in causing EC inflammation. Findings
from the proposed studies will allow us to determine whether epinephrine/β2-adrenergic receptor signaling can
be targeted to alleviate SA/IH-induced EC activation and the resulting cardiovascular disease.

## Key facts

- **NIH application ID:** 10409555
- **Project number:** 5P01HL144454-04
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Gokhan M. Mutlu
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $380,700
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409555

## Citation

> US National Institutes of Health, RePORTER application 10409555, Mechanisms Underlying Sympathetic Activation-dependent Endothelial Cell Activation by Chronic Intermittent Hypoxia (5P01HL144454-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10409555. Licensed CC0.

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