Dysregulated Smooth Muscle Cell BMPR2-ARRB2 Axis Causes Pulmonary Hypertension

Area of Science:

• Cardiovascular Biology
• Pulmonary Hypertension Pathophysiology
• Molecular Medicine

Background:

• Mutations in bone morphogenetic protein receptor 2 (BMPR2) are linked to pulmonary arterial hypertension (PAH).
• The role of BMPR2 in pulmonary artery smooth muscle cells (PASMC) in PAH pathogenesis is not fully understood, with research often focusing on endothelial cells.

Purpose of the Study:

• To investigate the functional and molecular consequences of BMPR2 deficiency in PASMC.
• To determine the relationship between decreased BMPR2 expression and the abnormal PASMC phenotype observed in PAH.

Main Methods:

• Generation of SMC-specific Bmpr2 knockout (BKO) mice.
• Assessment of pulmonary hypertension indices (echocardiography, RVSP, RVH) in BKO mice under normoxia, hypoxia, and recovery.
• Analysis of PASMC proliferation, contractility, and gene/protein expression from BKO mice, human PASMC with reduced BMPR2, and PAH patient-derived PASMC.

Main Results:

• BKO mice exhibited persistent pulmonary hypertension and sustained distal pulmonary artery muscularization after hypoxia.
• PASMC from mutant models showed reduced contractility, increased proliferation, and apoptosis resistance.
• A signaling pathway involving upregulated ARRB2, altered AKT/GSK3-beta/CTNNB1, and reduced RHOA/RAC1 was identified in PASMC with BMPR2 deficiency.
• Reducing ARRB2 levels restored normal PASMC function and prevented persistent pulmonary hypertension in BKO mice.

Conclusions:

• Loss of BMPR2 in PASMC leads to hypocontractility and hyperproliferation, contributing to PAH.
• Elevated ARRB2 in PASMC is a key mediator of the aberrant phenotype caused by BMPR2 deficiency.
• Targeting ARRB2 presents a potential therapeutic strategy to reverse or prevent PAH-associated PASMC dysfunction.