# Nox1-mediated transcriptional de-repression and activation of CXCL12 expression in hypoxic pulmonary endothelial cells and PAH

> **NIH NIH F32** · WEST VIRGINIA UNIVERSITY · 2020 · $65,310

## Abstract

Abstract
Pulmonary arterial hypertension (PAH) is a devastating disease with 5-year survival under 60%.
Recent attention has focused on a role for pulmonary endothelial cells (EC) injury and proliferation
in the initiation of vascular remodeling in PAH. However, the mechanisms in pulmonary ECs
driving proliferation and remodeling is poorly understood limiting therapeutic options. Our
laboratory has implicated a role for NADPH oxidase 1 (Nox1) in human pulmonary artery EC
(hPAEC) proliferation. However, the key downstream effectors of this pathway are still poorly
defined. Recently elevations in the chemokine CXCL12 has been associated with PAH and
disease severity. CXCL12 is well known in other pathologies to induce alterations in cellular
metabolism, migration and proliferation, all hallmarks of PAH vascular remodeling. Additionally,
transcriptional regulation of CXCL12 described in other cell types has the potential to be
modulated by Nox1-mediated signaling. However, the mechanisms of CXCL12 upregulation and
signaling pathways in hPAECs remain poorly understood. We will therefore examine the
hypothesis that hypoxia-mediated Nox1-signaling increases CXCL12, leading to alterations in
migration and proliferation in PAEC. To explore this hypothesis, we have designed in vitro and in
vivo experiments utilizing pharmacological agents and genetic perturbations. Our preliminary data
shows trending elevation of CXCL12 in our local PAH population measured in total lung lysates
and that hypoxia induces a >2-fold increase in CXCL12 expression in hPAECs. Using both gain
and loss of function approaches our preliminary data implicates two Nox1-signaling pathways
leading to the upregulation of CXCL12 in hypoxic hPAECs. This elevation in CXCL12 results in
altered migration and proliferation of hPAECs. To investigate these pathways in vivo we have
created a novel EC-specific inducible Nox1 knockout mouse. We hypothesize the loss of EC Nox1
will prevent PAH development while exogenous administration of CXCL12 will restore PAH in the
knockout mice. These studies will advance our knowledge of a causal role for CXCL12 in PAH
pathology, identify Nox1-mediated signaling pathways as key regulators of CXCL12, and suggest
Nox1 as a potential therapeutic target in PAH.

## Key facts

- **NIH application ID:** 9990112
- **Project number:** 1F32HL152534-01
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** Evan DeVallance
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 1
- **Project period:** 2020-08-31 → 2021-08-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990112

## Citation

> US National Institutes of Health, RePORTER application 9990112, Nox1-mediated transcriptional de-repression and activation of CXCL12 expression in hypoxic pulmonary endothelial cells and PAH (1F32HL152534-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9990112. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*