Contribution of oxidative stress to endothelial dysfunction in hereditary hemorrhagic telangiectasia
Bibliographic record
Abstract
Oxidative stress causes endothelial dysfunction and is implicated in the pathogenesis of cardiovascular diseases. Our studies suggested that reactive oxygen species (ROS) play a crucial role in hereditary hemorrhagic telangiectasia (HHT) disease, a vascular dysplasia affecting 1 in 5,000-8,000 people. Mutations in endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1) genes are responsible for HHT1 and HHT2 and are associated with arteriovenous malformations. ENG and ACVRL1 interact with endothelial nitric oxide synthase (eNOS) and regulate its activation. Mice heterozygous for these genes (Eng (+/-) and Acvrl1 (+/-)) show reduced ENG or ACVRL1 protein levels in endothelial cells causing eNOS uncoupling, generation of ROS rather than nitric oxide (NO•), leading to impaired NO• mediated vasodilation. ROS production is increased in several organs of Eng (+/-) and Acvrl1 (+/-) mice, including lungs, liver, and colon, affected in HHT. The major source of increased oxidative stress in these tissues is eNOS-derived ROS and not mitochondrial or NADPH oxidase-dependent ROS. Eng (+/-) and Acvrl1 (+/-) mice also develop with age signs of pulmonary arterial hypertension attributable to eNOS-derived ROS, which was preventable by antioxidant treatment. To date, only one pilot study has been carried out in HHT patients, and it showed beneficial effects of antioxidant therapy on epistaxis. We suggest that more clinical studies are warranted to investigate whether antioxidants would prevent, delay or attenuate manifestations of disease in individuals with HHT, based on our experimental data in mouse models.
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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) | 0.001 | 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 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".