# A ROLE FOR EYA3 IN VASCULAR REMODELING AND PULMONARY ARTERIAL HYPERTENSION

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $636,205

## Abstract

Project Summary
Pulmonary Hypertension (PH) is a pathophysiologic condition characterized by elevated
pressure in the pulmonary arteries. Pulmonary arterial hypertension (WHO Group I PH;
PAH) is a particularly severe form of PH frequently associated with right heart failure and
premature death. There is no cure, and treatments only target the symptoms.
Approximately 50% of PAH patients die within 5 years of diagnosis. There is therefore a
compelling, unmet need for new therapeutic strategies.
Pulmonary vascular remodeling is the defining pathological feature of PAH. It leads to
occlusion of distal pulmonary arterioles, with accompanying increase in pulmonary
vascular resistance. Vascular remodeling is promoted by the survival and proliferation of
pulmonary arterial vascular cells under conditions of oxidative stress and in the presence
of DNA damage. Here we provide evidence that the Eyes Absent protein (EYA3)
promotes survival of DNA damaged cells facing a survival-versus-apoptosis decision.
EYA3 is a druggable and mechanistically unique protein tyrosine phosphatase (PTP)
present at elevated levels in pulmonary arterial smooth muscle cells isolated from PAH
patients. In proof of principle studies, we show that transgenic mice harboring an
inactivating mutation in the EYA3 PTP domain are significantly protected from vascular
remodeling in a chronic hypoxia model, and that inhibitors of EYA3 PTP activity reverse
vascular remodeling in a rat model of experimental angio-obliterative PH.
The overall goal of this project is to establish the EYA3-PTP as a disease-modifying
target whose function in the pathophysiology of PAH can be targeted by available
inhibitors. This will be a critical milestone in pre-clinical drug target validation and will be
achieved through the use of genetic and pharmacological approaches in the following
two Specific Aims:
Aim I: To elucidate the molecular mechanism(s) through which EYA3 promotes the
pathogenesis of PAH we will use a murine chronic hypoxia model. Hemodynamic and
histopathological analyses upon cell-type specifc EYA3 deletion will be conducted to
identify the cell-autuonomous roles of EYA3 in vascular remodeling. Single-cell
transcriptomics and phospho-protein analyses will be used to delineate the molecular
mechanims contributing to vascular remodeling.
Aim II: To establish the effectiveness of EYA3-PTP inhibitors in reversing established
vascular remodeling we will use a rat model of angio-obliterative PAH and evaluate the
most safe and effective modes of EYA3-targeted pharmacological intervention.
The overall impact of this proposal is that it will define a targetable signaling
mechanism that contributes to the characteristic pulmonary vascular pathobiology in
PAH, demonstrate that EYA3-PTP inhibitors are viable lead compounds for the
development of PAH therapeutics, and provide insights into a previously unexplored
molecular mechanism contributing to PAH pathology.

## Key facts

- **NIH application ID:** 10171900
- **Project number:** 5R01HL152094-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** RASHMI S. HEGDE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $636,205
- **Award type:** 5
- **Project period:** 2020-06-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171900

## Citation

> US National Institutes of Health, RePORTER application 10171900, A ROLE FOR EYA3 IN VASCULAR REMODELING AND PULMONARY ARTERIAL HYPERTENSION (5R01HL152094-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10171900. Licensed CC0.

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