title: Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension.
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.
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Lu
authors.initials: L
authors.lastname: Long
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Ormiston
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Xudong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Southwood
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gräf
authors.affiliation: University of Lincoln, School of Life Sciences, Lincoln, UK.
authors.forename: Rajiv D
authors.identifier: 0000000192470744
authors.initials: RD
authors.lastname: Machado
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mueller
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kinzel
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lai Ming
authors.initials: LM
authors.lastname: Yung
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Janine M
authors.initials: JM
authors.lastname: Wilkinson
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Moore
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Kylie M
authors.identifier: 0000000314054694
authors.initials: KM
authors.lastname: Drake
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Micheala A
authors.identifier: 0000000273909181
authors.initials: MA
authors.lastname: Aldred
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Yu
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Upton
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D003720:Densitometry; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D055879:Gene Knock-In Techniques; D055427:Growth Differentiation Factor 2 / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D016686:Monocrotaline; D010766:Phosphorylation / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013599:Systole / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D055427:Growth Differentiation Factor 2; D016686:Monocrotaline; D048031:JNK Mitogen-Activated Protein Kinases; D052006:Bone Morphogenetic Protein Receptors, Type II