Inhibition of BMPER Mitigates Pulmonary Hypertension by Modulating LRP1-YAP Interaction in Smooth Muscle Cells

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Pulmonary Hypertension Research

Background:

• Bone morphogenetic protein-binding endothelial regulator (BMPER) is a secreted protein crucial for vascular development.
• Mutations in the bone morphogenetic protein (BMP) pathway are linked to pulmonary arterial hypertension (PAH).
• The specific role of BMPER in PAH pathogenesis was previously unknown.

Purpose of the Study:

• To investigate the expression and function of BMPER in Group 1 pulmonary arterial hypertension.
• To elucidate the mechanisms by which BMPER influences pulmonary vascular remodeling.
• To assess the therapeutic potential of targeting BMPER in PAH.

Main Methods:

• Assessed BMPER expression in human PAH patient samples.
• Utilized in vivo (mouse models) and in vitro approaches to study BMPER's role in vascular remodeling.
• Examined BMPER's effect on pulmonary artery smooth muscle cell proliferation and right ventricular pressures.
• Investigated the mechanistic link between BMPER, YAP, and LRP1.

Main Results:

• BMPER levels were elevated in PAH lungs and correlated with pulmonary vascular resistance.
• BMPER depletion in mice attenuated pulmonary vascular remodeling and reduced right ventricular pressures.
• BMPER overexpression induced spontaneous PAH development in mice.
• BMPER promotes YAP activation via LRP1, contributing to pulmonary artery smooth muscle cell proliferation.

Conclusions:

• Secreted BMPER is a key regulator of pulmonary vascular remodeling in PAH.
• BMPER's mechanism involves YAP activation mediated by LRP1.
• Inhibition of BMPER presents a potential novel therapeutic strategy for pulmonary arterial hypertension.