# Metabolic regulation of Ca2+ entry and endothelial-mesenchymal transition in pulmonary arterial hypertension

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $403,000

## Abstract

PROJECT SUMMARY Pulmonary arterial hypertension (PAH) is a lethal disease characterized by abnormal
proliferation of microvascular endothelial cells (MVECs) in the distal blood vessels of the lung. There are
currently no therapies that target the underlying endothelial dysfunction in PAH. Mitochondrial dysfunction,
increased intracellular calcium ([Ca2+]i) and endothelial-mesenchymal transition (EndMT) are important
pathogenic abnormalities observed in MVECs isolated from patients with PAH, but the mechanisms that link
these cellular abnormalities is unknown. In MVECs isolated from rats undergoing Sugen/Hypoxia (SuHx), an
experimental form of PAH (SuHx-MVECs), our prior work and current preliminary data suggest a)
mitochondrial dysfunction recapitulating those seen in human PAH ECs, b) increased mitochondrial reactive
oxygen species (mtROS) and β-hydroxybutyrate (BOHB), c) increased activation of the transient receptor
potential vanilloid-4 (TRPV4) channel and increased intracellular calcium ([Ca2+]i), d) EndMT and e) increased
proliferation. Further, we also observe specific shifts in metabolism (increased use of anaerobic respiration as
well as an increase in fatty acid oxidation), suggesting a metabolic basis for mitochondrial dysfunction in SuHx-
MVECs. Our preliminary data now suggest specific roles for two metabolic byproducts of increased fatty acid
oxidation – BOHB and mtROS - in sensitizing and activating TRPV4, respectively. Thus, we hypothesize that,
in PAH, a shift in MVEC mitochondrial metabolism from glycolysis to fatty acid oxidation promotes mtROS and
BOHB generation, leading to TRPV4 activation and consequently, Ca2+-dependent activation of EndMT and
proliferation. Using MVECs isolated from rats, mice and humans with and without PAH, as well as in vivo
experiments utilizing various novel transgenic rats and mice, we propose the three independent aims centered
around the following questions: 1) How does increased fatty acid oxidation promote TRPV4 activation in
MVECs; 2) Is TRPV4 activation necessary and sufficient to induce EndMT; and 3) What is the impact of
TRPV4 loss or BOHB supplementation on EndMT development in vivo. To accomplish these aims, we plan on
utilizing a variety of methods ranging from fluorescent live-cell imaging of MVECs isolated from WT and
transgenic mice and rats, in vitro studies in human MVECs from PAH patients (and controls), and in vivo
lineage-tracing studies to examine EndMT development in rodent models of PAH. Completion of these aims
will provide novel insight into the interplay between fatty acid metabolism, Ca2+ homeostasis and EndMT in
normal MVECs and role of the metabolic dysfunction and increased [Ca2+]I and EndMT in PAH.

## Key facts

- **NIH application ID:** 10295118
- **Project number:** 1R01HL151530-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Karthik Suresh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $403,000
- **Award type:** 1
- **Project period:** 2021-09-20 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10295118

## Citation

> US National Institutes of Health, RePORTER application 10295118, Metabolic regulation of Ca2+ entry and endothelial-mesenchymal transition in pulmonary arterial hypertension (1R01HL151530-01A1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10295118. Licensed CC0.

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