Penetrance of Severe Pulmonary Arterial Hypertension in Response to Vascular Endothelial Growth Factor Receptor 2 Blockade in a Genetically Prone Rat Model Is Reduced by Female Sex
Bibliographic record
Abstract
Background We have previously reported important strain differences in response to SU5416 (SU, a vascular endothelial growth factor receptor 2 inhibitor) in rats and have identified a specific colony of Sprague‐Dawley rats that are hyperresponsive (SD HR ) to SU alone and develop severe pulmonary arterial hypertension (PAH) with a single injection of SU, even in the absence of hypoxia. Interestingly, SD HR rats exhibit incomplete penetrance of the severe PAH phenotype with an “all‐or‐none” response to SU alone, which provides a unique opportunity to assess the influence of female sex and sex hormones on susceptibility to PAH after endothelial injury in a genetically prone model. Methods and Results SD HR rats were injected with SU (20 mg/kg SC) and, in the absence of hypoxia, 72% of male but only 27% of female rats developed severe PAH at 7 weeks, which was associated with persistent endothelial cell apoptosis. This sex difference in susceptibility for severe PAH was abolished by ovariectomy. Estradiol replacement, beginning 2 days before SU (prevention), inhibited lung endothelial cell apoptosis and completely abrogated severe PAH phenotype in both male and ovariectomized female rats, while progesterone was only protective in ovariectomized female rats. In contrast, delayed treatment of SD HR rats with established PAH with estradiol or progesterone (initiated at 4 weeks post‐SU) failed to reduce lung endothelial cell apoptosis or improve PAH phenotype. Conclusions Female sex hormones markedly reduced susceptibility for the severe PAH phenotype in response to SU alone in a hyperresponsive rat strain by abolishing SU‐induced endothelial cell apoptosis, but did not reverse severe PAH in established disease.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".