Abstract 344: Endothelin-1 Overexpression Exaggerates Diabetes-induced Endothelial Dysfunction
Bibliographic record
Abstract
Objective: Vascular disease associated with endothelial dysfunction is a major cause of morbidity in patients with type-1 diabetes. Endothelin (ET)-1 plays a role in diabetes-induced vascular complications, since ET-1 type A receptor blockade reduces diabetes-induced vascular injury. However, whether ET-1 contributes to diabetes-induced endothelial dysfunction remains unproven. We hypothesized that vascular ET-1 overexpression will exaggerate diabetes-induced endothelial dysfunction. Methods: Diabetes was induced by streptozotocin treatment (STZ, 55 mg/kg/day, ip) for 5 days in 6-week-old male wild-type (WT) mice and in mice overexpressing ET-1 restricted to the endothelium (eET-1). Mice were studied 14 weeks later. Blood was collected to determine glucose. Mesenteric artery reactivity and remodeling were evaluated using pressurized myography and aortic fibronectin expression by immnunofluorescence. Results: STZ-induced diabetes was confirmed by a 3-fold increase in glycemia in WT and eET-1 ( P <0.001). Diabetes impaired endothelium-dependent relaxation (EDR) reponses to acetylcholine in WT (60.9±6.4% vs 83.9±3.4%, P <0.05) and eET-1 (48.6±5.1% vs 81.5±5.2%, P <0.001). EDR impairment was exaggerated in eET-1 compared to WT ( P <0.05). Meclofenamic acid, an inhibitor of cyclooxygenase, increased EDR in eET-1 compared to WT (78.4±9.4% vs 66.7±3.2%, P <0.01), which was not observed in diabetic mice. L-NAME, an inhibitor of nitric oxide (NO) synthase, completely blocked EDR in WT, eET-1 and diabetic WT, but not in diabetic eET-1 (4.1±1.6%, 6.4±5.7%, 2.2±4.6% and 26.6±4.6%, P <0.05). Apamin plus Tram34, inhibitors of endothelium-dependent hyperpolarization inhibited EDR in the four groups. Endothelium-independent relaxation to sodium nitroprusside, a NO donor, was similar in the four groups. Diabetes reduced media/lumen in WT (2.7±0.3 vs 3.6±0.3, P <0.05) and eET-1 (2.9±0.2 vs 3.8±0.3, P <0.05). Diabetes decreased aortic fibronectin expression in WT (94.0±11.0 vs. 151.9±21.8 RFU/μm 2 , P <0.05) and eET-1 (66.3±8.7 vs. 146.6±20.7 RFU/μm 2 , P <0.05). Conclusion: ET-1 contributes to alterations in several pathways mediating endothelium-dependent relaxation in type-1 diabetes, leading to exaggerated endothelial dysfunction.
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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 | 0.000 |
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".