Cardiomyocyte GC1 Mediates Estrogenic Angiogenesis in Right Heart Remodeling.

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Sex Differences in Disease

Background:

• Right ventricular (RV) dysfunction is a major cause of mortality in heart failure and pulmonary hypertension.
• Women exhibit better RV function and survival than men, a phenomenon often attributed to estrogen.
• The precise mechanisms by which estrogen confers this protection remain incompletely understood.

Purpose of the Study:

• To investigate the role of cardiomyocyte NO-sensitive soluble guanylyl cyclase 1 (sGC1) in mediating female-specific adaptive RV remodeling under pressure overload.
• To elucidate the molecular pathways involved in estrogen-dependent RV protection.

Main Methods:

• Adult male and female mice with cardiomyocyte-specific GC1 deficiency and controls underwent pulmonary artery banding (PAB) or sham surgery.
• RV function was assessed using echocardiography, pressure-volume loops, and treadmill testing.
• Single-nucleus RNA sequencing and endothelial coculture assays were employed to identify intercellular signaling pathways.

Main Results:

• Female controls with PAB adapted RV contractility, preserving RV-PA coupling, while female GC1 knockout, ovariectomized females, and male PAB mice developed severe RV dysfunction.
• Maladapted RVs showed cardiomyocyte hypertrophy, fibrosis, and capillary rarefaction; the capillary-to-cardiomyocyte ratio strongly correlated with RV function.
• Cardiomyocyte sGC1 was identified as central to VEGF-VEGFR proangiogenic signaling from cardiomyocytes to endothelial cells.

Conclusions:

• A novel estrogen- and cardiomyocyte sGC1-dependent pathway mitigates capillary rarefaction and preserves RV-PA coupling during RV pressure overload.
• This proangiogenic mechanism contributes to sex-specific differences in RV remodeling.
• The findings may guide the development of targeted therapies for RV dysfunction.