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Nat Med. 2015 Jul;21(7):777-85. doi: 10.1038/nm.3877. Epub 2015 Jun 15.

Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension.

Author information

1
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
2
Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge, UK.
3
University of Lincoln, School of Life Sciences, Lincoln, UK.
4
Novartis Institutes for Biomedical Research, Basel, Switzerland.
5
Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
6
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Abstract

Genetic evidence implicates the loss of bone morphogenetic protein type II receptor (BMPR-II) signaling in the endothelium as an initiating factor in pulmonary arterial hypertension (PAH). However, selective targeting of this signaling pathway using BMP ligands has not yet been explored as a therapeutic strategy. Here, we identify BMP9 as the preferred ligand for preventing apoptosis and enhancing monolayer integrity in both pulmonary arterial endothelial cells and blood outgrowth endothelial cells from subjects with PAH who bear mutations in the gene encoding BMPR-II, BMPR2. Mice bearing a heterozygous knock-in allele of a human BMPR2 mutation, R899X, which we generated as an animal model of PAH caused by BMPR-II deficiency, spontaneously developed PAH. Administration of BMP9 reversed established PAH in these mice, as well as in two other experimental PAH models, in which PAH develops in response to either monocrotaline or VEGF receptor inhibition combined with chronic hypoxia. These results demonstrate the promise of direct enhancement of endothelial BMP signaling as a new therapeutic strategy for PAH.

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PMID:
26076038
PMCID:
PMC4496295
DOI:
10.1038/nm.3877
[Indexed for MEDLINE]
Free PMC Article

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