Effect of Hyperhomocystinemia and Hypertension on Endothelial Function in Methylenetetrahydrofolate Reductase–Deficient Mice
Bibliographic record
Abstract
OBJECTIVE: We evaluated the effect of hyperhomocystinemia and angiotensin (Ang) II on vascular function and structure in methylenetetrahydrofolate reductase knockout mice (Mthfr+/-). METHODS AND RESULTS: Mthfr+/- and controls (Mthfr+/+) received Ang II (400 ng/kg per min SC) or saline (14 days). Blood pressure, similar in Mthfr+/- and Mthfr+/+, was increased by Ang II. Acetylcholine- and bradykinin-induced relaxations were impaired in mesenteric resistance arteries (pressurized myograph) in Mthfr+/- and in Ang II-infused Mthfr+/+ mice and additionally blunted in Ang II-infused Mthfr+/- mice. The inhibition by L-NAME on acetylcholine was reduced in Mthfr+/- and in Ang II-Mthfr+/+ and absent in Ang II-Mthfr+/- mice. In these groups, vitamin C improved the response to acetylcholine and restored the inhibition by L-NAME. The media to lumen ratio of small arteries, similar in Mthfr+/- and Mthfr+/+, was increased by Ang II. Vascular NADPH oxidase activity, similar in Mthfr+/- and Mthfr+/+, increased after Ang II infusion. Vascular xanthine oxidase activity was also similar in Mthfr+/- and Mthfr+/+. Superoxide production in the aorta was reduced by sepiapterin and by L-NAME, suggesting that reduced bioavailability of tetrahydrobiopterin and uncoupling of nitric oxide synthase were the origin of increased reactive oxygen species in this model. CONCLUSIONS: Mthfr+/- mice show endothelial dysfunction of mesenteric vessels probably attributable to a reduced nitric oxide bioavailability caused by oxidative excess due to uncoupling of nitric oxide synthase without vascular structural alterations. Concurrent Ang II-induced hypertension additionally reduced nitric oxide, increased NADPH oxidase activity, and induced structural alterations. Our findings suggest additive adverse effect of Ang II-dependent hypertension and hyperhomocystinemia on endothelial function.
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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) | 0.001 | 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 | 0.000 |
| 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".