Cardiomyocyte GC1 Mediates Estrogenic Angiogenesis in Right Heart Remodeling
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".