# Estrogen signaling and energy metabolism in pulmonary arterial hypertension

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $768,635

## Abstract

PROJECT SUMMARY
 Pulmonary arterial hypertension (PAH) is a progressively fatal disease with a female predominance.
We previously showed that human PAH is strongly associated with reduced expression of the estrogen
metabolism gene CYP1B1 and increase in the estrogen metabolite 16αOHE, which is highly estrogenic. Both
females and males with BMPR2-associated PAH (BMPR2-PAH) and idiopathic PAH have elevated 16αOHE.
 While Bmpr2 mutant mice develop PAH with variable penetrance induced, addition of 16αOHE
significantly amplifies penetrance and PAH severity. However, both pharmacologic blockade of estrogens and
estrogen receptor (ESR) knock down approaches prevent PAH development. The data thus suggest that
increased 16αOHE (and perhaps other estrogens), via ESR signaling, contribute to PAH pathogenesis.
 Concurrent with the exploration of estrogen metabolites in PAH, we and others are actively exploring
the association of altered energy metabolism, including insulin resistance, with PAH. Insulin resistance and
abnormal energy metabolism are features of BMPR2-PAH and idiopathic PAH subtypes, despite a lack of overt
clinical co-morbid conditions. Intriguingly, while 16αOHE is vasodilatory and anti-inflammatory (features that
should reduce PAH), it has also been associated with molecular insulin resistance and metabolic disturbances,
including reductions in PPARγ and GLUT4 expression, and reduced mitochondrial oxygen consumption rates.
In preliminary studies, we found that estrogen antagonism in mice prevents PAH and these molecular defects.
 Exploring the possibility that 16αOHE drives PAH, we found that increased lung expression of the
miR29 family, known to regulate energy metabolism, associates with PAH penetrance and is amplified by
16αOHE. Further, disruption of miR29 activity by a miR29 antagonist prevented PAH and preserved metrics of
normal energy metabolism (including rescue of PPARγ and GLUT4) in Bmpr2 mutant mice treated with
16αOHE. Thus, 16αOHE may amplify PAH via miR29-associated PPARγ suppression and altered metabolism.
 We hypothesize that that highly estrogenic compounds, including 16αOHE, contribute to PAH by
dysregulating pulmonary vascular energy metabolism via suppression of PPARγ. We will explore this
hypothesis with three aims: (1) To determine whether the estrogen 16αOHE associates with insulin resistance
and elevated miR29 levels in humans with PAH; (2) To test the hypothesis that 16αOHE dysregulates energy
metabolism primarily through suppression of PPARγ; (3) To determine the mechanisms by which 16αOHE
suppresses PPARγ. This proposal will elucidate the mechanisms by which a highly estrogenic sex hormone
profile (e.g., towards highly estrogenic compounds such as 16αOHE) results in PAH via the promotion of
systemic and molecular features of insulin resistance and other derangements in energy metabolism. Given
that estrogens may support heart function but promote PAH, ways to precisely target the correct person, or the
correct pa...

## Key facts

- **NIH application ID:** 10076635
- **Project number:** 5R01HL134802-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Eric Douglas Austin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $768,635
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10076635

## Citation

> US National Institutes of Health, RePORTER application 10076635, Estrogen signaling and energy metabolism in pulmonary arterial hypertension (5R01HL134802-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10076635. Licensed CC0.

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