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Excessive TGF-\u03b2\u2013mediated signaling is implicated in the pathogenesis of pulmonary arterial hypertension, based in part on the ability of broad inhibition of activin-like kinase (ALK) receptors 4\/5\/7 recognizing TGF-\u03b2, activin, growth and differentiation factor, and nodal ligands to attenuate experimental pulmonary hypertension (PH). These broad inhibition strategies do not delineate the specific contribution of TGF-\u03b2 versus a multitude of other ligands, and their translation is limited by cardiovascular and systemic toxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>We tested the impact of a soluble TGF-\u03b2 type II receptor extracellular domain expressed as an immunoglobulin\u2013Fc fusion protein (TGFBRII-Fc), serving as a selective TGF-\u03b21\/3 ligand trap, in several experimental PH models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Signaling studies used cultured human pulmonary artery smooth muscle cells. PH was studied in monocrotaline-treated Sprague-Dawley rats, SU5416\/hypoxia\u2013treated Sprague-Dawley rats, and SU5416\/hypoxia\u2013treated C57BL\/6 mice. PH, cardiac function, vascular remodeling, and valve structure were assessed by ultrasound, invasive hemodynamic measurements, and histomorphometry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>TGFBRII-Fc is an inhibitor of TGF-\u03b21 and TGF-\u03b23, but not TGF-\u03b22, signaling. In vivo treatment with TGFBRII-Fc attenuated Smad2 phosphorylation, normalized expression of plasminogen activator inhibitor-1, and mitigated PH and pulmonary vascular remodeling in monocrotaline-treated rats, SU5416\/hypoxia\u2013treated rats, and SU5416\/hypoxia\u2013treated mice. Administration of TGFBRII-Fc to monocrotaline-treated or SU5416\/hypoxia\u2013treated rats with established PH improved right ventricular systolic pressures, right ventricular function, and survival. No cardiac structural or valvular abnormalities were observed after treatment with TGFBRII-Fc.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings are consistent with a pathogenetic role of TGF-\u03b21\/3, demonstrating the efficacy and tolerability of selective TGF-\u03b2 ligand blockade for improving hemodynamics, remodeling, and survival in multiple experimental PH models.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201510-1955oc","type":"journal-article","created":{"date-parts":[[2016,4,26]],"date-time":"2016-04-26T12:43:47Z","timestamp":1461674627000},"page":"1140-1151","source":"Crossref","is-referenced-by-count":137,"title":["A Selective Transforming Growth Factor-\u03b2 Ligand Trap Attenuates Pulmonary Hypertension"],"prefix":"10.1093","volume":"194","author":[{"given":"Lai-Ming","family":"Yung","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Nikolic","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel D.","family":"Paskin-Flerlage","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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