# Paracrine Action of BMP3 in Pulmonary Hypertension

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2022 · $473,502

## Abstract

PROJECT ABSTRACT/SUMMARY
Paracrine Action of BMP3 in Pulmonary Hypertension
Pulmonary arterial hypertension (PAH) is a severe vascular disease characterized by persistent precapillary
pulmonary hypertension, leading to right heart failure and death. Despite intense research in the last decades
PH remains an incurable disease with a high morbidity and mortality. New directions and therapies to improve
understanding and treatment of PAH are desperately needed.
Although evidence demonstrates the importance of the Bone Morphogenetic Protein (BMP) signaling pathway
in PAH, our current understanding of the exact pathophysiological role of several members of this pathway
remains limited. In this R01 we propose detailed functional and mechanistic studies to understand the role of
BMP3 in PAH. We hypothesize that PASMC-derived BMP3 inhibits PAEC dysfunction and pathological
pulmonary vascular remodeling. Based on robust preliminary studies, we propose testing this central
hypothesis with 3 specific aims.
Aim 1 will define BMP3 regulation in PAH and its effects in vitro. We will assess the levels of pulmonary BMP3
levels and circulating BMP3 levels in lung and serum of patients with clinical PAH and of PAH-diseased
animals. We will also determine whether sex affects pulmonary BMP3 expression in humans and rodents, and
we will investigate the effect of PASMC-derived BMP3 on PAEC function in cocultures of PASMCs and PAECs
isolated from non-PAH and PAH patients.
Aim 2 will characterize the in vivo effects of cell-specific BMP3 deletion and of BMP3 upregulation. We will
provide a detailed characterization of the cardiopulmonary phenotypes of SMC- and EC-specific BMP3 KO
mice. We will also examine the effects of exogenous recombinant BMP3 on PAH in the Sugen/Hypoxia model
in rats. Using a novel approach, which we have demonstrated to be highly specific and efficient for protein
overexpression in the lung (i.e. chemically modified mRNAs (modRNAs)), we will assess whether BMP3
modRNA reverses PAH in the Sugen/Hypoxia model in rats.
Aim 3 will dissect the molecular mechanisms of BMP3. We will perform a series of in vitro and in vivo studies
to determine the mechanism(s) of BMP3 regulation and to define BMP3 mechanism(s) of action. Promoter
activity assays, co-immunoprecipitation experiments, GST pull down assays, quantitative PCR measurements
and western blot analyses will determine the pathways implicated in BMP3 signals. Cocultures of PASMCs and
PAECs and lungs from BMP3-KO mice and from rats overexpressing BMP3 in vivo will determine the
pathways implicated in BMP3 signals.

## Key facts

- **NIH application ID:** 10344203
- **Project number:** 1R01HL160963-01
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Yassine Sassi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $473,502
- **Award type:** 1
- **Project period:** 2022-08-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10344203

## Citation

> US National Institutes of Health, RePORTER application 10344203, Paracrine Action of BMP3 in Pulmonary Hypertension (1R01HL160963-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10344203. Licensed CC0.

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