# BMPR2 mutations, Neointimal Transformation and Pulmonary Arterial Hypertension

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2021 · —

## Abstract

Patients served by the Veterans Health Administration who have chronic cardiopulmonary conditions are at high
risk for death because of pulmonary hypertension (PH). A particularly dangerous form of PH, referred to as
pulmonary arterial hypertension (PAH), is a vascular disease with high prevalence and poor survival among US
veterans. PAH is characterized by gene variants, chronic inflammation and an occlusive remodeling of the
vascular intima (neointima). Heterozygous germline mutations in BMPR2 (bone morphogenetic protein receptor
2) is the principle genetic risk factor for hereditary PAH. There is an unmet need to understand how
environmental cues induce PAH in otherwise healthy BMPR2 mutation carriers.
We recently showed in a new ‘2-hit’ rat model that Bmpr2 mutations, when coupled with pulmonary inflammation,
elicit severe PAH in otherwise phenotypically-silent Bmpr2+/- mutant rats. PAH in this model features a
proliferative and inflammatory neointima with characteristics shared by human disease. TGF-b blockade
ameliorates advanced PAH and neointimal transformation in Bmpr2+/- animals and is a promising clinical therapy.
Pilot single cell RNA-seq analyses of the disease rat lungs revealed that Bmpr2 mutations and an inflamed lung
microenvironment cause a ‘transcriptional convergence’ of endothelial cells (ECs, originating from pulmonary
arteries, arterioles and capillaries) to form the transformed neointima. Based on these results, we postulate
that PAH occurs in Bmpr2 mutants because discrete endothelial transcriptional programs are modulated
and result in an inflamed neointima.
This proposal explores how genetic and environmental triggers may lead to neointimal formation and PAH at the
cellular and molecular levels; proposed studies also search for druggable targets driving EC transformation
following TGF-b treatment. Specific Aim 1 evaluates how Bmpr2 deficiency causes transcriptional
convergence of ECs to form the PAH neointima and has three subaims which are to establish a molecular
atlas of rat lungs in health and PAH using cutting-edge single molecular techniques (Aim 1a), then to elucidate
the cellular origins of neointima by tracking specific endothelial lineage cells in evolving disease (Aim 1b), and
finally to identify molecular programs responsible for the formation and maintenance of vascular lesions (Aim
1c). Specific Aim 2 explores how BMPR2 deficiency in human pulmonary arterial ECs provokes
proliferative endothelial inflammation and focuses on the influence of BMPR2 deficiency on inflammatory 5-
lipoxygenase (5-LO), NF-kB and IL-6 signaling. Here, the mechanisms by which BMPR2 insufficiency induces
5-LO epigenetic and post-translational modification, NF-kB transcriptional activities and classical- or trans-IL-6
signaling will be assessed. Specific Aim 3 tests whether TGF-b blockade reverses PAH by eliminating
transcriptionally-convergent ECs (i.e., neointimal cells) in the lungs of Bmpr2 mutant rats. This aim
investigates whe...

## Key facts

- **NIH application ID:** 10260902
- **Project number:** 1I01BX005628-01
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** Mark Robert Nicolls
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10260902

## Citation

> US National Institutes of Health, RePORTER application 10260902, BMPR2 mutations, Neointimal Transformation and Pulmonary Arterial Hypertension (1I01BX005628-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10260902. Licensed CC0.

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