BMPR2 Dosage Gates BMP9/10 Signaling Output in Pulmonary Artery Endothelium

Area of Science:

• Molecular Biology
• Cardiovascular Research
• Cell Signaling

Background:

• Pulmonary arterial hypertension (PAH) involves pulmonary artery endothelium and smooth muscle dysfunction.
• Loss-of-function mutations in the Bone Morphogenetic Protein Receptor 2 (BMPR2) gene are a primary cause of heritable PAH.
• The precise mechanisms linking reduced BMPR2 to PAH pathogenesis are not fully understood.

Purpose of the Study:

• To investigate how BMPR2 levels influence endothelial signaling and functional responses.
• To elucidate the role of BMPR2 in mediating BMP9/10 signaling in pulmonary artery endothelial cells (PAECs).

Main Methods:

• BMPR2 expression was modulated in human PAECs.
• Ligand-dependent SMAD1/5/8 signaling, cell proliferation, and caspase-3/7 activity were assessed.
• Responses were evaluated under varying BMPR2 levels and in the presence of Activin type II receptor blockade.

Main Results:

• BMP9 and BMP10 robustly activated SMAD1/5/8 signaling and promoted PAEC proliferation.
• A ~50% reduction in BMPR2 attenuated BMP9/10-induced signaling and proliferation, increasing caspase-3/7 activity.
• BMPR2 overexpression enhanced BMP9/10 signaling and proliferation; responses were sensitive to Activin type II receptor blockade under limiting BMPR2 conditions.

Conclusions:

• Physiological BMPR2 levels are essential for maintaining homeostatic BMP9/10 signaling in pulmonary artery endothelium.
• A receptor-dosage model explains how BMPR2 levels impact endothelial function and contribute to PAH.
• Findings provide a framework for understanding context-dependent pathway effects in PAH pathogenesis.