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Pulmonary arterial hypertension (PAH) is a rare, life-limiting disease where imbalances in the TGFb superfamily pathways have causal roles in hereditary and idiopathic forms. These pathways are emerging attractive candidates for therapeutic intervention but there is an unmet need for clinically relevant and practical biomarkers that can measure target engagement. A major challenge has been the inaccessibility of lung tissue in disease for molecular profiling. Here we explore the surrogate capacity of peripheral blood BMP pathway-specific markers. Plasma proteomic analysis demonstrates widespread pleiotropic alterations of TGFß/BMP modulators. Downstream BMPR-II canonical and non-canonical signaling is altered and measurable in whole blood, and transcriptomic signatures cluster by discrete BMPR-II gene modules. We present discovery and international replication cohorts for the transcriptomic BMPR-II signaling signatures and derive a composite transcriptomic biomarker panel that is repeatable, reproducible, longitudinally stable and expressed in correlated gene modules in PAH which associate with clinical outcomes, most notably mortality. The assay performance characteristics of the biomarker panel make it feasible for early phase, target engagement clinical trials and we have utilised it in a pilot study of sotatercept-treated patients that suggests the therapy does not mechanistically rebalance/increase BMPR-II pathway signaling, but rather shows a reduction, likely due to depletion of circulating BMP9 and BMP10.