Endothelium-derived C-type natriuretic peptide offsets the pathogenesis of pulmonary hypertension

Area of Science:

• Cardiovascular Biology
• Pulmonary Medicine
• Molecular Cardiology

Background:

• C-type natriuretic peptide (CNP) is crucial for systemic homeostasis, influencing vascular remodeling and cardiac function.
• Pulmonary hypertension (PH) involves complex pathobiology affecting the pulmonary circulation and right ventricle.
• Natriuretic peptide receptor (NPR) signaling pathways are potential targets for therapeutic intervention in cardiovascular diseases.

Purpose of the Study:

• To investigate the protective role of endogenous CNP in the pulmonary circulation and right ventricle during PH development.
• To explore the therapeutic potential of targeting NPR signaling in PH.
• To elucidate the specific contributions of endothelial and cardiomyocyte-derived CNP to PH pathogenesis.

Main Methods:

• Utilized knockout mouse models (endothelium-restricted CNP knockout, cardiomyocyte-specific CNP knockout, global NPR-C knockout) exposed to a hypoxia/Sugen (SuHx) model of PH.
• Administered exogenous CNP via osmotic minipump to mice with established PH.
• Assessed PH severity by measuring right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), and RV fibrosis.

Main Results:

• Endothelial-specific CNP deficiency exacerbated PH development, RVH, and fibrosis in the SuHx model.
• Global NPR-C deficiency specifically worsened RVH and fibrosis, but not RVSP.
• Cardiomyocyte-specific CNP deficiency did not significantly alter the PH phenotype.
• Exogenous CNP administration effectively reduced RVSP and promoted cardiopulmonary anti-remodeling signaling.

Conclusions:

• Endogenous CNP, particularly from endothelial sources, plays a protective role against the development of pulmonary hypertension and right ventricle remodeling.
• Targeting CNP-dependent NPR-B and NPR-C signaling pathways demonstrates therapeutic potential for managing PH and associated RV dysfunction.