Androgens drive microvascular endothelial dysfunction in women with polycystic ovary syndrome: role of the endothelin B receptor
Why this work is in the frame
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Bibliographic record
Abstract
Key points Polycystic ovary syndrome (PCOS) is a complex syndrome with cardiovascular risk factors, including obesity and insulin resistance. PCOS is also associated with high androgens, increases the risk of cardiovascular dysfunction in women. Due to the complexity of PCOS, had it has been challenging to isolate specific causes of the cardiovascular dysfunction. Our measure of cardiovascular dysfunction (endothelial dysfunction) was most profound in lean women with PCOS. The endothelin‐1‐induced vasodilation in these PCOS subject, was dependent on the ET B R but was not NO‐dependent. We also demonstrated oestrogen administration improved endothelial function in lean and obese women with PCOS likely because oestrogen increased NO availability. Our studies indicate a primary role for androgens in cardiovascular dysfunction in PCOS. Abstract Endothelin‐1 (ET‐1) is an indicator of endothelial injury and dysfunction and is elevated in women with androgen excess polycystic ovary syndrome (AE‐PCOS). The endothelin B receptor (ET B R) subtype mediates vasodilatation, but is blunted in women with PCOS. We hypothesized that androgen drives endothelial dysfunction in AE‐PCOS women and oestradiol (EE) administration reverses these effects. We assessed microvascular endothelial function in women with (7 lean and 7 obese) and without AE‐PCOS (controls, 6 lean, 7 obese). Only obese AE‐PCOS women were insulin resistant (IR). We evaluated cutaneous vascular conductance (%CVC max ) with laser Doppler flowmetry during low dose intradermal microdialysis ET‐1 perfusions (1, 3, 4, 5 and 7 pmol) with either lactated Ringer solution alone, or with ET B R (BQ‐788), or nitric oxide (NO) inhibition ( l ‐NAME). Log[ET‐1]–%maxCVC dose–response curves demonstrated reduced vasodilatory responses to ET‐1 in lean AE‐PCOS (logED 50 , 0.59 ± 0.08) versus lean controls (logED 50 , 0.49 ± 0.09, P < 0.05), but not compared to obese AE‐PCOS (logED 50 , 0.65 ± 0.09). ET B R inhibition decreased ET‐1‐induced vasodilatation in AE‐PCOS women (logED 50 , 0.64 ± 0. 22, P < 0.05). This was mechanistically observed at the cellular level, with ET‐1‐induced, DAF‐FM‐measurable endothelial cell NO production, which was abrogated by dihydrotestosterone in an androgen receptor‐dependent manner. EE augmented the cutaneous vasodilating response to ET‐1(logED 50 0.29 ± 0.21, 0.47 ± 0.09, P < 0.05 for lean and obese, respectively). Androgens drive endothelial dysfunction in lean and obese AE‐PCOS. We propose that the attenuated ET‐1‐induced vasodilatation in AE‐PCOS is a consequence of androgen receptor‐mediated, suppressed ET B R‐stimulated NO production, and is reversed with EE.
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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 | 0.000 | 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) | 0.001 | 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 it