{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T20:05:31Z","timestamp":1793131531630,"version":"4.5.0"},"reference-count":86,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>Overactive activin\/growth and differentiation factor (GDF) signaling is one of the many pathogenic drivers of progressive vascular remodeling and right ventricular (RV) failure in pulmonary arterial hypertension (PAH). In contrast, bone morphogenic proteins (BMPs) play a crucial role in maintaining vascular homeostasis. The clinical success of sotatercept, an activin receptor (ActR)IIA-Fc ligand trap, has paved the way for targeting activin\/GDF signaling in PAH. However, sotatercept has limitations, including severe thrombocytopenia and erythrocytosis, which may increase the risk of hyperviscosity syndrome (HVS) and bleeding. Here, we demonstrated that a modified ActRIIB-Fc ligand trap, KER-012\/RKER-012, exhibited BMP-sparing properties while retaining binding to activin\/GDF ligands, similar to the wild-type ActRIIA and ActRIIB ligand traps. We also demonstrated that hypoxia increased susceptibility to HVS-related bleeding and mortality in response to erythropoietin (EPO)-induced erythrocytosis and severe thrombocytopenia in Sugen rats. Unlike sotatercept, KER-012\/RKER-012 did not elicit erythrocytosis or thrombocytopenia; therefore, a modified ActRIIB-Fc ligand trap like KER-012\/RKER-012 could reduce the risk of potential HVS effect and bleeding. We also showed that RKER-012 can attenuate experimental PAH by targeting multiple components of a complex pathobiology, such as dysregulated cell growth, endothelial-to-mesenchymal transition (EndoMT), extracellular matrix (ECM) remodeling, inflammation, immune cell modulation, and fibrosis. This evidence highlights the potential to optimize an activin receptor ligand trap to target overactive activin\/GDF signaling in PAH while sparing BMP signaling and minimizing the risk of bleeding, vascular integrity, and erythrocytosis. Ultimately, this approach could improve pulmonary vascular remodeling to alleviate PAH.<\/jats:p>","DOI":"10.3389\/fcvm.2026.1827438","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T04:50:43Z","timestamp":1782276643000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["RKER-012, a modified ActRIIB-Fc ligand trap with BMP sparing properties, attenuates pathological features of experimental pulmonary arterial hypertension"],"prefix":"10.3389","volume":"13","author":[{"given":"R. Keith","family":"Babbs","sequence":"first","affiliation":[{"name":"Keros Therapeutics","place":["Lexington, MA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne","family":"Ishimwe","sequence":"additional","affiliation":[{"name":"Keros Therapeutics","place":["Lexington, MA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Materna","sequence":"additional","affiliation":[{"name":"Keros Therapeutics","place":["Lexington, MA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ffolliott M.","family":"Fisher","sequence":"additional","affiliation":[{"name":"Keros Therapeutics","place":["Lexington, MA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tandicka","family":"Nurse","sequence":"additional","affiliation":[{"name":"Keros Therapeutics","place":["Lexington, MA, United 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