{"doi":"10.1126/scitranslmed.aaz5660","title":"ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension","abstract":"Human genetics, biomarker, and animal studies implicate loss of function in bone morphogenetic protein (BMP) signaling and maladaptive transforming growth factor-β (TGFβ) signaling as drivers of pulmonary arterial hypertension (PAH). Although sharing common receptors and effectors with BMP/TGFβ, the function of activin and growth and differentiation factor (GDF) ligands in PAH are less well defined. Increased expression of GDF8, GDF11, and activin A was detected in lung lesions from humans with PAH and experimental rodent models of pulmonary hypertension (PH). ACTRIIA-Fc, a potent GDF8/11 and activin ligand trap, was used to test the roles of these ligands in animal and cellular models of PH. By blocking GDF8/11- and activin-mediated SMAD2/3 activation in vascular cells, ACTRIIA-Fc attenuated proliferation of pulmonary arterial smooth muscle cells and pulmonary microvascular endothelial cells. In several experimental models of PH, prophylactic administration of ACTRIIA-Fc markedly improved hemodynamics, right ventricular (RV) hypertrophy, RV function, and arteriolar remodeling. When administered after the establishment of hemodynamically severe PH in a vasculoproliferative model, ACTRIIA-Fc was more effective than vasodilator in attenuating PH and arteriolar remodeling. Potent antiremodeling effects of ACTRIIA-Fc were associated with inhibition of SMAD2/3 activation and downstream transcriptional activity, inhibition of proliferation, and enhancement of apoptosis in the vascular wall. ACTRIIA-Fc reveals an unexpectedly prominent role of GDF8, GDF11, and activin as drivers of pulmonary vascular disease and represents a therapeutic strategy for restoring the balance between SMAD1/5/9 and SMAD2/3 signaling in PAH.","journal":"Science Translational Medicine","year":2020,"id":49699,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":237,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9474,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":241046,"name":"Peiran Yang","orcid":"0000-0002-4635-1215","position":1,"is_corresponding":false},{"id":243711,"name":"Sachindra Raj Joshi","orcid":null,"position":2,"is_corresponding":false},{"id":241047,"name":"Zachary M. Augur","orcid":"0000-0001-9664-7498","position":3,"is_corresponding":false},{"id":241048,"name":"Stephanie S. Kim","orcid":"0000-0002-6453-0823","position":4,"is_corresponding":false},{"id":241049,"name":"Geoffrey A. Bocobo","orcid":"0000-0002-7392-5376","position":5,"is_corresponding":false},{"id":241050,"name":"Teresa Dinter","orcid":"0000-0003-4764-501X","position":6,"is_corresponding":false},{"id":241051,"name":"Luca Troncone","orcid":"0000-0002-2056-8758","position":7,"is_corresponding":false},{"id":243712,"name":"Po-Sheng Chen","orcid":null,"position":8,"is_corresponding":false},{"id":241052,"name":"Megan McNeil","orcid":"0000-0002-3844-8324","position":9,"is_corresponding":false},{"id":241053,"name":"Mark Southwood","orcid":"0000-0002-3493-9599","position":10,"is_corresponding":false},{"id":34717,"name":"Sergio Poli","orcid":"0000-0001-5442-3189","position":11,"is_corresponding":false},{"id":241054,"name":"John L. Knopf","orcid":"0000-0001-9083-7258","position":12,"is_corresponding":false},{"id":34736,"name":"Iván O. Rosas","orcid":"0000-0003-4622-618X","position":13,"is_corresponding":false},{"id":243713,"name":"Dianne Sako","orcid":null,"position":14,"is_corresponding":false},{"id":241055,"name":"R. Scott Pearsall","orcid":"0000-0002-7095-5246","position":15,"is_corresponding":false},{"id":243714,"name":"John D. Quisel","orcid":null,"position":16,"is_corresponding":false},{"id":241056,"name":"Gang Li","orcid":"0000-0002-4611-6602","position":17,"is_corresponding":false},{"id":241057,"name":"Ravindra Kumar","orcid":"0000-0001-5295-9684","position":18,"is_corresponding":false},{"id":241058,"name":"Paul B. Yu","orcid":"0000-0003-2145-4944","position":19,"is_corresponding":false},{"id":241045,"name":"Lai‐Ming Yung","orcid":"0000-0002-3650-2980","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-18T20:37:28.027635Z","pmid":"32404506","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}