Sex‐Specific Role of Endothelin‐A Receptors in the Cardiac Susceptibility to Ischemia/Reperfusion Insult in Adult Offspring Exposed to Prenatal Hypoxia
Bibliographic record
Abstract
Introduction Fetal hypoxia, a common consequence of complicated pregnancies, leads to the development of cardiac dysfunction in adult offspring by impairing cardiac tolerance to an ischemia/reperfusion (I/R) insult. Extensive evidence demonstrates that cardiac I/R upregulates the endothelin‐1 (ET‐1) system leading to elevated levels of ET‐1 (a peptide with potent physiological and pathophysiological effects on the cardiovascular system). Active ET‐1 exerts its effects via the endothelin‐A receptors (ET A R; of which enhanced activation has been associated with impaired post‐I/R cardiac function) and endothelin‐B receptors (ET B R; which are essential for post‐I/R cardiac recovery). However, whether activation of ET A R contributes to cardiac dysfunction in adult offspring exposed to prenatal hypoxia is unknown. We hypothesize that, in adult offspring exposed to prenatal hypoxia, cardiac ET A R expression is increased, and its inhibition improves post‐I/R cardiac recovery. Methods Pregnant Sprague‐Dawley rats (n=4‐6 dams/group) were exposed to normoxia (21% O 2 ; normoxia) or hypoxia (11% O 2 ; p‐hypoxia) from gestational day 15‐21 (term=22 days). Cardiac function was assessed ex vivo in 4‐month old male and female offspring (n=1‐2 offspring/dam) by subjecting isolated hearts to I/R (25 min. of ischemia with 40 min. of reperfusion). The contribution of ET A R to cardiac dysfunction was assessed by pre‐infusion with an ET A R antagonist (ABT‐627) before I/R (ABT‐627 was recirculated during reperfusion). ET A R and ET B R levels were assessed in non‐ischemic left ventricle tissues by Western blotting. Data (mean±SEM) were compared by two‐way ANOVA (Sidak's post hoc test), or by unpaired t‐test. Results : ABT‐627 induced a dramatic reduction in cardiac recovery after I/R in prenatally hypoxic males compared to their respective controls (control: 60.5±16.3% vs ABT‐627: 4.4±2.6%, p=0.009), without effect in normoxic males. In contrast, ABT‐627 improved I/R recovery in prenatal hypoxia‐exposed females (control: 53.5±10.6% vs ABT‐627: 87±5.6%, p=0.05) with no effect in normoxic females. In males, exposure to prenatal hypoxia did not alter cardiac ET A R levels, but decreased ET B R levels compared to the normoxic group (normoxia: 100±3.2% vs p‐hypoxia: 70.6±4%, p=0.0003), without changes in females. Conclusion Prenatal hypoxia alters the cardiac ET‐1 system in a sex‐specific manner. Inhibition of ET A R in prenatally hypoxic males impaired cardiac recovery post‐I/R, potentially due to lower ET B R expression; while cardiac recovery was improved by ET A R inhibition in females. Activation of ET A R may thus be essential for cardiac tolerance to I/R in prenatally hypoxic males, while it may contribute to the development of cardiac dysfunction in females. Our data suggests that developmental influences and sex differences need to be considered during the implementation of therapeutic strategies to prevent the long‐term effects of pregnancy complications on offspring cardiac health.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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) | 0.003 | 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 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".