# Mechanisms of HIF-Induced Microvascular Endothelial Dysfunction in Pulmonary Arterial Hypertension

> **NIH NIH F32** · JOHNS HOPKINS UNIVERSITY · 2022 · $77,039

## Abstract

PROJECT SUMMARY
The objectives of this NRSA application are to 1) develop research skills that will allow the candidate to become
a successful physician-scientist and 2) investigate the mechanisms by which hypoxia-inducible factor 2 (HIF-2)
causes pulmonary arterial hypertension (PAH). PAH is a highly morbid disease despite recent advancements in
therapy. Clinically, increased pulmonary artery pressure, caused in part by hyperproliferative lung microvascular
endothelial cells (MVEC), leads to right ventricular failure and death. Rigorous preclinical studies have uncovered
a critical role of HIF-2 in PAH development, but the specific mechanisms are unknown. In tumor cells, HIF-2
causes mitochondrial dysfunction and augmented cell growth. In pulmonary MVECs, our lab showed that
mitochondrial dysfunction causes activation of the Ca2+ channel transient receptor potential vanilloid type 4
(TRPV4), increased intracellular Ca2+ concentration ([Ca2+]i) and MVEC hyperproliferation. The causes of
mitochondrial dysfunction in PAH MVEC – and whether HIF-2 plays any role in the observed abnormalities – are
not known, and will be the focus of this application. The long-term goal of this proposal is to identify pathways of
HIF-2-induced MVEC dysfunction that can be targeted for the treatment of PAH. Thus, the purpose of this project
is to examine the mechanisms by which HIF-2 causes MVEC dysfunction. The candidate’s preliminary studies
have shown that non-specific HIF stabilization in pulmonary MVECs causes mitochondrial fragmentation. In
Specific Aim 1, the candidate will assess the effects of HIF-2 over-expression and deletion on several measures
of mitochondrial dysfunction, including fragmentation and ROS production. In Specific Aim 2, using live Ca2+
imaging, immunoblots, RT-PCR and biotinylation assays, the candidate will assess the role of HIF-2 in
modulating MVEC [Ca2+]i. In Aim 3, the candidate will test whether HIF-2 regulates MVEC hyperproliferation and,
if so, whether this occurs via mitochondrial dysfunction or changes in [Ca2+]i. The goal of these experiments is
to determine whether HIF-2 causes mitochondrial dysfunction, increased [Ca2+]i and hyperproliferation in PAH
MVECs; completion of this project will provide a training platform to gain skills that will prove invaluable in the
candidate’s transition to independence at the end of fellowship.

## Key facts

- **NIH application ID:** 10531127
- **Project number:** 5F32HL154672-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Ryan Belecanech
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $77,039
- **Award type:** 5
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10531127

## Citation

> US National Institutes of Health, RePORTER application 10531127, Mechanisms of HIF-Induced Microvascular Endothelial Dysfunction in Pulmonary Arterial Hypertension (5F32HL154672-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10531127. Licensed CC0.

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