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

Long, Lu and Ormiston, Mark L. and Yang, Xudong and Southwood, Mark and Gräf, Stefan and Machado, Rajiv D. and Mueller, Matthias and Kinzel, Bernd and Yung, Lai Ming and Wilkinson, Janine M. and Moore, Stephen D. and Drake, Kylie M. and Aldred, Micheala A. and Yu, Paul B. and Upton, Paul D. and Morrell, Nicholas W. (2015) Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nature Medicine, 21 (7). pp. 777-785. ISSN 1078-8956

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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.

Keywords:Endothelial BMPR-II, BMPRII, BMP9, Pulmonary arterial hypertension, Apoptosis, Monolayer integrity, Endothelial cells, JCNotOpen
Subjects:A Medicine and Dentistry > A100 Pre-clinical Medicine
C Biological Sciences > C521 Medical Microbiology
Divisions:College of Science > School of Life Sciences
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ID Code:18456
Deposited On:21 Aug 2015 11:20

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