December 2025, Circulation Research: Cardiomyocyte GC1 Mediates Estrogenic Angiogenesis in Right Heart Remodeling

Continuing our long-standing productive collaboration with Emily Tsai's group at Columbia, this publication identifying a unique mechanism for female specific adaptation to right ventricular remodeling. While cardiology has traditionally spent the vast majority of focus and effort on the left ventricle, which controls systemic circulation, right ventricular function is a critical predictor of heart failure, especially that with preserved ejection fraction. Here, Emily's group generated mice with cardiomyocyte specific deletion of Gc1, a guanylyl cyclase, which was shown to be critical for female specific protection of RV function following pressure overload. Our role in the study was to generate and analyze single nucleus RNA sequencing data from the RVs of these mice, most notably demonstrating proangiogenic signaling from cardiomyocytes to vascular endothelium in the adaptive remodeling seen in females.

Abstract from DOI: 10.1161/CIRCRESAHA.124.326070

Background: Right ventricular (RV) dysfunction increases mortality in heart failure and pulmonary hypertension. However, women demonstrate better RV function and survival than men. This difference is attributed to estrogen, though mechanistic details remain unclear. Given estrogen's stimulation of NO production, we investigated whether and how cardiomyocyte NO-sensitive GC1 (soluble guanylyl cyclase) mediates female-specific, adaptive RV pressure-overload remodeling.

Methods: Adult male and female mice with cardiomyocyte-specific GC1 deficiency (cardiomyocyte-specific knockout) and littermate controls underwent pulmonary artery banding (PAB) or thoracotomy (Sham). At 6-week postsurgery, RV function was assessed via echocardiography, pressure-volume loops, and treadmill testing. RV function, histopathology, and transcript profiles were compared across sex, genotype, and surgical group. Single-nucleus RNA sequencing of RV tissue was performed to identify putative cardiomyocyte GC1-mediated cell-cell communication in adaptive RV pressure-overload remodeling. Endothelial coculture assays with controls versus cardiomyocyte-specific knockout cardiomyocytes evaluated estrogen and cardiomyocyte GC1-dependence of the identified intercellular signaling.

Results: Female control PAB mice adapted RV contractility to overcome RV pressure-overload, thereby preserving RV-PA coupling. In contrast, female cardiomyocyte-specific knockout, ovariectomized female controls, and male PAB developed severe RV dysfunction with RV-PA uncoupling. These groups with maladapted RVs had marked cardiomyocyte hypertrophy, interstitial fibrosis, and capillary rarefaction; female control PAB had minimal changes. Among histological features, the capillary-to-cardiomyocyte ratio showed the strongest correlation with RV function. Ratios were similar between female control PAB and Sham, but abnormally low in all other PAB. Single-nucleus RNA sequence and coculture analyses revealed that cardiomyocyte GC1 is central to Vegf (vascular endothelial growth factor)-Vegfr (Vegf receptor) proangiogenic signaling from cardiomyocytes to endothelial cells in the adaptively remodeled, pressure-overloaded RV.

Conclusions: We identified a novel estrogen- and cardiomyocyte GC1-dependent pathway that mitigates capillary rarefaction, maintaining normal capillary-to-cardiomyocyte ratio and preserving RV-PA coupling under RV pressure-overload. This proangiogenic, estrogen- and cardiomyocyte GC1-dependent mechanism contributes to sex-specific differences in RV remodeling and may inform the development of targeted therapies for RV dysfunction.