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

• Published in: Nature medicine Vol. 21; no. 7; pp. 777 - 785
• Main Authors: Long, Lu, Ormiston, Mark L, Yang, Xudong, Southwood, Mark, Gräf, Stefan, Machado, Rajiv D, Mueller, Matthias, Kinzel, Bernd, Yung, Lai Ming, Wilkinson, Janine M, Moore, Stephen D, Drake, Kylie M, Aldred, Micheala A, Yu, Paul B, Upton, Paul D, Morrell, Nicholas W
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2015; Nature Publishing Group
• Subjects: 13/106; 13/2; 13/21; 13/31; 13/51; 13/95; 14/1; 38/39; 38/61; 631/443/592/75/593; 64/60; 692/308/575; Aging - pathology; Animal models; Animals; Apoptosis - drug effects; Biomedicine; Blood; Bone Morphogenetic Protein Receptors, Type II - metabolism; Bone morphogenetic proteins; Cancer Research; Cell Membrane Permeability - drug effects; Cell receptors; Cellular signal transduction; Densitometry; Development and progression; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Gene Expression Profiling; Gene Knock-In Techniques; Genes; Genetic aspects; Growth Differentiation Factor 2 - pharmacology; Heart Ventricles - drug effects; Heart Ventricles - pathology; Heart Ventricles - physiopathology; Humans; Hypertension; Hypertension, Pulmonary - genetics; Hypertension, Pulmonary - pathology; Hypertension, Pulmonary - physiopathology; Hypoxia; Immunoblotting; Infectious Diseases; JNK Mitogen-Activated Protein Kinases - metabolism; Male; Metabolic Diseases; Mice, Inbred C57BL; Molecular Medicine; Monocrotaline; Mutation; Neurosciences; Phosphorylation - drug effects; Physiological aspects; Pulmonary Artery - drug effects; Pulmonary Artery - pathology; Pulmonary Artery - physiopathology; Pulmonary hypertension; Rats; Rats, Sprague-Dawley; Rodents; Systole - drug effects; Transcription, Genetic - drug effects; United Kingdom
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3877

BMP9 activates signaling through the BMPR-II receptor in endothelial cells and reverses established disease in three animal models of pulmonary hypertension, thus pointing to a potential new treatment for this disease. 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.