Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension
Ormiston, Mark L.
Machado, Rajiv D.
Yung, Lai Ming
Wilkinson, Janine M.
Moore, Stephen D.
Drake, Kylie M.
Aldred, Micheala A.
Upton, Paul D.
Morrell, Nicholas W.Note: Order does not necessarily reflect citation order of authors.
MetadataShow full item record
CitationLong, L., M. L. Ormiston, X. Yang, M. Southwood, S. Gräf, R. D. Machado, M. Mueller, et al. 2015. “Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension.” Nature medicine 21 (7): 777-785. doi:10.1038/nm.3877. http://dx.doi.org/10.1038/nm.3877.
AbstractGenetic 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. We identified 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 bearing mutations in BMPR-II. In vivo, we report the spontaneous generation of PAH in a mouse model bearing a heterozygous knock-in of a human BMPR-II mutation, R899X. Administration of BMP9 reversed established PAH in Bmpr2+/R899X mice, as well as in models of disease developed 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 novel therapeutic strategy for PAH.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:24983945
- HMS Scholarly Articles