{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:34:27Z","timestamp":1791516867034,"version":"4.3.4"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2019,4,1]],"date-time":"2019-04-01T00:00:00Z","timestamp":1554076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["HL079943"],"award-info":[{"award-number":["HL079943"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["HL131910"],"award-info":[{"award-number":["HL131910"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["HL132742"],"award-info":[{"award-number":["HL132742"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["AR057374"],"award-info":[{"award-number":["AR057374"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["T32HL007604"],"award-info":[{"award-number":["T32HL007604"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["DK108370"],"award-info":[{"award-number":["DK108370"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["DK098079"],"award-info":[{"award-number":["DK098079"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>BMP9 (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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To determine how an acquired deficiency of BMP9 signaling might contribute to PAH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Plasma 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>BMP9 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>BMP9 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201807-1236oc","type":"journal-article","created":{"date-parts":[[2018,10,12]],"date-time":"2018-10-12T16:53:08Z","timestamp":1539363188000},"page":"891-902","source":"Crossref","is-referenced-by-count":109,"title":["Bone Morphogenetic Protein 9 Is a Mechanistic Biomarker of Portopulmonary Hypertension"],"prefix":"10.1093","volume":"199","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2823-897X","authenticated-orcid":false,"given":"Ivana","family":"Nikolic","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3650-2980","authenticated-orcid":false,"given":"Lai-Ming","family":"Yung","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4635-1215","authenticated-orcid":false,"given":"Peiran","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0120-4630","authenticated-orcid":false,"given":"Rajeev","family":"Malhotra","sequence":"additional","affiliation":[{"name":"Division of Cardiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel D.","family":"Paskin-Flerlage","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4764-501X","authenticated-orcid":false,"given":"Teresa","family":"Dinter","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey A.","family":"Bocobo","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen E.","family":"Tumelty","sequence":"additional","affiliation":[{"name":"Pfizer Centers for Therapeutic Innovation, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Faugno","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Tufts Medical Center, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Troncone","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan E.","family":"McNeil","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuli","family":"Huang","sequence":"additional","affiliation":[{"name":"Therapy for Rare and Neglected Diseases Program, National Center for Advancing Translational Sciences, Rockville, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn R.","family":"Coser","sequence":"additional","affiliation":[{"name":"Pfizer Centers for Therapeutic Innovation, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol S. 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