# Estrogen receptor-alpha effects on right ventricular vascular density and angiogenesis in pulmonary hypertension

> **NIH VA I01** · RLR VA MEDICAL CENTER · 2020 · —

## Abstract

Pulmonary hypertension (PH) and right ventricular (RV) dysfunction are extremely common in veterans. Up to
80% of veterans with chronic obstructive pulmonary disease, pulmonary fibrosis, sleep disordered breathing or
LV dysfunction (either systolic or diastolic) suffer from PH. Better RV function and female sex have been linked
to improved survival in PH, and female patients exhibit better RV function than their male counterparts. This
proposal builds on the scientific premise that even though RV function and female sex are major determinants
of survival in PH, no RV-specific or sex steroid-directed therapies exist. Endothelial cell (EC) dysfunction and
impaired angiogenesis play a major role in the development of RV failure, and data obtained in the previous
funding period demonstrate that the female sex steroid 17β-estradiol (E2) increases capillary density in the RV
and stimulates angiogenesis in cultured cardiac ECs. The goal of this proposal is to identify novel and
therapeutically targetable mechanisms by which E2 exerts protective effects on RV EC function in PH. We
provide evidence that E2 exerts its RV EC-protective effects via its receptor ERα, and suggest a new
mechanism by which ERα activates bone morphogenetic protein receptor 2 (BMPR2) signaling to upregulate
apelin, a potent angiogenesis mediator and EC survival factor, whose regulation in the RV is not yet known.
Based on these findings, we now put forward the novel hypothesis that E2 improves RV function in PH by
ERα- and BMPR2-dependent up-regulation of EC apelin. We propose the following specific aims: 1) To
establish that E2 increases capillary density in the RV via BMPR2-dependent increases in EC apelin, and 2)
To identify the contribution of ERα to increasing capillary density in the RV. We generated a novel ERα
knockout rat that will enable us to study the role of ERα in the rat pulmonary artery banding model, thus
avoiding the pitfalls of prior studies of sex hormone signaling performed in PH models without RV failure.
These studies will be complemented by studies of BMPR2-deficient rats and apelin-deficient mice. These loss-
of-function studies will be accompanied by studies in which we interrogate the therapeutic potential of ERα
agonists, BMPR2 activators and apelin receptor agonists. We will complement these in vivo studies with
experiments in RV ECs isolated from rodents with RV failure and from patients with compensated (adaptive) or
decompensated (maladaptive) RV hypertrophy. Endpoints investigated will include RV function and structure
(by pressure volume loops and echocardiography), exercise capacity (measured as VO2 max via treadmill
running), RV capillary density (quantified using unbiased stereology and lectin staining), angiogenesis assays
(matrigel tube formation and transwell migration), BMPR2 and apelin signaling pathways, as well as mediators
of angiogenesis and EC survival and apoptosis. The proposed studies are significant, since they will 1) identify
ER...

## Key facts

- **NIH application ID:** 9861192
- **Project number:** 5I01BX002042-07
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** Tim Lahm
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9861192

## Citation

> US National Institutes of Health, RePORTER application 9861192, Estrogen receptor-alpha effects on right ventricular vascular density and angiogenesis in pulmonary hypertension (5I01BX002042-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9861192. Licensed CC0.

---

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