# Context-specific angiogenic signaling in the pulmonary vasculature

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $604,402

## Abstract

This project describes a research program to ascertain the functions of the BMP9-BMPR2-ALK1
signaling axis in pulmonary vascular biology, and to determine its contribution to pulmonary
arterial hypertension (PAH). Loss-of-function mutations in genes encoding the BMP9 signaling
complex in endothelial cells—BMPR2, ALK1, co-receptor ENG, GDF2, and downstream effector
SMAD9—have been implicated in heritable PAH, while the acquired deficiency of these factors
and of downstream SMAD1/5/9 signaling have been hallmarks of non-genetic forms (PH). The
mechanisms by which BMPR2/ALK1 signaling regulates homeostasis of the pulmonary
vasculature are not known, and the manner in which dysregulated BMP9 signaling may
predisposes to PAH remains incompletely understood. In support of a protective role of BMP9
signaling, treatment with recombinant BMP9 ligand attenuates PH and pulmonary vascular
remodeling in several models of PH, while deficiency of circulating BMP9 is associated with
portopulmonary hypertension. Paradoxically, treatment with ALK1-Fc, a BMP9 ligand trap, also
ameliorates experimental PH, suggesting Janus-like, context-sensitive effects of BMP9
signaling in PAH. Aim 1 of this program includes detailed mechanistic studies to discern how
distinct co-receptors and effectors recruited by BMP9 signaling may elicit disparate functions in
pulmonary vascular cells. Aim 2 investigates the physiologic effects of these signals using in
vitro and in vivo models of pulmonary vascular barrier function. Aim 3 examines how selective
engagement of various components of the BMP9 receptor complex may impact experimental
PH and pulmonary vascular remodeling. These studies leverage the extensive experience in
selective modulation and targeting of the BMP/TGFb signaling pathway, and novel
pharmacologic probes designed to engage various components of the signaling pathway in a
highly selective and translatable fashion. This program is supported by proof-of-concept studies
using human cells, and state-of-the-art models. This project builds upon the demonstrated
therapeutic potential of modulating BMP/TGFb family signaling for the treatment of pulmonary
vascular disease and may generate novel strategies that would overcome the limitations of
current approved and investigational therapies.

## Key facts

- **NIH application ID:** 10450846
- **Project number:** 5R01HL159443-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** PAUL B YU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $604,402
- **Award type:** 5
- **Project period:** 2021-07-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450846

## Citation

> US National Institutes of Health, RePORTER application 10450846, Context-specific angiogenic signaling in the pulmonary vasculature (5R01HL159443-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10450846. Licensed CC0.

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