Solving an enigma: the BMP-9/10 axis as a key regulator of pulmonary vascular resilience.

The circulating ligands bone morphogenetic protein (BMP)-9 and BMP-10 are emerging as dual regulators of pulmonary and systemic vascular biology. Acting through activin receptor-like kinase 1 (ALK1), BMP receptor type II (BMPRII) and endoglin receptor complexes, they maintain endothelial quiescence and vascular tone under physiological conditions. Yet, the same axis can turn pathogenic when its intensity, timing or cellular context are altered. We propose viewing BMP-9/10 not as a linear protective pathway but as a bimodal system in which both deficiency and hyperactivation disrupt vascular homeostasis, leading to distinct phenotypes such as obstructive pulmonary arterial remodeling in pulmonary arterial hypertension (PAH), intrapulmonary vasodilatation in hepatopulmonary syndrome (HPS), and arteriovenous shunting in hereditary haemorrhagic telangiectasia (HHT). The clinical success of sotatercept, an activin signaling inhibitor with partial BMP-ligand trap properties, underscores the translational potential of therapeutically "retuning" this pathway rather than globally enhancing it. Understanding when BMP-9/10 signaling protects and when it becomes pathogenic will be crucial for designing next-generation interventions that stabilize, instead of destabilize, pulmonary vascular integrity.