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. 2023 Feb 19;24(4):4147. doi: 10.3390/ijms24044147

Figure 2.

Figure 2

BMP signaling pathway. (A). Dysregulation of the BMP signaling pathway produces an imbalance between anti-proliferative and pro-proliferative routes in pulmonary arterial hypertension. Decreased BMPR2 activity leads to reduced BMP9/10-mediated signaling, diminished activation of Smad1/5/8 and reduction in the transcription of anti-proliferative genes, causing an increase in apoptosis and loss of the endothelial barrier integrity. This promotes the upregulation of pro-proliferative routes by production of activin A and GDF that bind to the ALK—ActRIIA/B complex and activate the pro-proliferative Smad2/3 pathway. This route also increases the expression of the BMP antagonists, gremlin-1 and noggin, further downregulating the BMPR2 pathway. (B). Sotatercept is a fusion protein comprising the extracellular domain of the activin receptor type IIA attached to the Fc domain of human IgG1. It acts as a ligand trap by binding activins and GDF and thereby restoring the balance between pro-proliferative and anti-proliferative BMP pathways. ActRIIA/B: activin receptor type IIA; ALK: activin receptor-like kinase; BMP: bone morphogenic protein; BMPR2: bone morphogenic protein receptor type-2; GDF: growth differentiation factor; pSmad: phosphorylated Smad; Smad: small mothers against decapentaplegic protein.