• Ivana Nikolic, Lai-Ming Yung, Peiran Yang, Rajeev Malhotra, Samuel D Paskin-Flerlage, Teresa Dinter, Geoffrey A Bocobo, Kathleen E Tumelty, Anthony J Faugno, Luca Troncone, Megan E McNeil, Xiuli Huang, Kathryn R Coser, Carol S C Lai, Paul D Upton, Marie Jose Goumans, Roham T Zamanian, C Gregory Elliott, Arthur Lee, Wei Zheng, Stephen P Berasi, Christine Huard, Nicholas W Morrell, Raymond T Chung, Richard W Channick, Kari E Roberts, and Paul B Yu.
• 1 Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
• Am. J. Respir. Crit. Care Med. 2019 Apr 1; 199 (7): 891902891-902.

RationaleBMP9 (bone morphogenetic protein 9) is a circulating endothelial quiescence factor with protective effects in pulmonary arterial hypertension (PAH). Loss-of-function mutations in BMP9, its receptors, and downstream effectors have been reported in heritable PAH.ObjectivesTo determine how an acquired deficiency of BMP9 signaling might contribute to PAH.MethodsPlasma levels of BMP9 and antagonist soluble endoglin were measured in group 1 PAH, group 2 and 3 pulmonary hypertension (PH), and in patients with severe liver disease without PAH.Measurements And Main ResultsBMP9 levels were markedly lower in portopulmonary hypertension (PoPH) versus healthy control subjects, or other etiologies of PAH or PH; distinguished PoPH from patients with liver disease without PAH; and were an independent predictor of transplant-free survival. BMP9 levels were decreased in mice with PH associated with CCl4-induced portal hypertension and liver cirrhosis, but were normal in other rodent models of PH. Administration of ALK1-Fc, a BMP9 ligand trap consisting of the activin receptor-like kinase-1 extracellular domain, exacerbated PH and pulmonary vascular remodeling in mice treated with hypoxia versus hypoxia alone.ConclusionsBMP9 is a sensitive and specific biomarker of PoPH, predicting transplant-free survival and the presence of PAH in liver disease. In rodent models, acquired deficiency of BMP9 signaling can predispose to or exacerbate PH, providing a possible mechanistic link between PoPH and heritable PAH. These findings describe a novel experimental model of severe PH that provides insight into the synergy between pulmonary vascular injury and diminished BMP9 signaling in the pathogenesis of PAH.

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