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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This work was supported by grants from the British Heart Foundation RG/13/4/30107 (N.W.M.), CH/09/001/25945 (N.W.M.), PG/11/10/28724 (P.D.U. and N.W.M.) and FS/12/39/29653 (M.L.O.); a Fondation Leducq Transatlantic Network of Excellence Award (N.W.M. and P.B.Y.); US National Institutes of Health grants 5R01-AR057374 (P.B.Y.), 5K08-HL079943 (P.B.Y.) and R01-HL098199 (M.A.A.); a Howard Hughes Medical Institute Early Career Physician Scientist Award (P.B.Y.) and a UK National Institute for Health Research Healthcare Science Fellowship (M.S.). The UK National Institute for Health Research Cambridge Biomedical Research Centre and Cell Phenotyping Hub provided infrastructure support.
The authors declare no competing financial interests.
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Long, L., Ormiston, M., Yang, X. et al. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med 21, 777–785 (2015). https://doi.org/10.1038/nm.3877
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