BMP9-mediated regulation of endothelin-1 requires integrated SMAD1/5 and SMAD2/3 signaling

BMP9 has recently emerged as a novel therapeutic target with an ongoing Phase 2 clinical trial testing an anti-BMP9 antibody for efficacy in PAH ( NCT06137742 ). The mechanisms by which BMP9 contributes to pulmonary vascular disease are thought to include its regulation of Endothelin-1 (ET-1), an established therapeutic target in PAH. We show that BMP9 potently regulates ET-1 transcription via transactivation of TGFβ1 effector SMAD3 via BMP receptors BMPR2 and ALK1, suggesting that pleiotropic effects of this growth factor cytokine result from non-canonical activation of BMP and TGFβ signaling pathways, with implications for its roles in physiology, and the rationale for its therapeutic modulation for PAH.