Abstract 3633: Flow-induced Dilation is Mediated by Akt-dependent Activation of eNOS-derived H2O2 in Mouse Cerebral Arteries
Bibliographic record
Abstract
Introduction . Endothelial nitric oxide synthase (eNOS) produces superoxide leading to H 2 O 2 -dependent dilations to acetylcholine (ACh) in isolated mouse cerebral and human coronary arteries. Akt increases eNOS activity responsible for flow-mediated dilation (FMD). It is unknown, however, if endogenous H 2 O 2 mediates FMD. Hypothesis . Akt-dependent activation of eNOS leads to the production of functionally relevant levels of H 2 O 2 responsible for FMD. Methods . Cerebral arteries (100 to 150 μm in diameter) were isolated from 12±2 week-old C57Bl/6 male mice. FMD (0 to 10 μl/min, 2-mu;l step-increase at constant internal pressure of 60 mm Hg; shear stress = 0 to 50 dyn/cm 2 ) were induced in vessels pre-constricted with phenylephrine (30 μM) at a pO 2 value of 150 mm Hg using a gas mixture of 12% O 2 , 5% CO 2 , 83% N 2 . Simultaneously to diameter acquisition, H 2 O 2 or NO production was detected by the fluorescent dyes CMH 2 CFDA or DAF-2, respectively. Results are expressed as mean±SEM of n = 6 to 8 mice per experiment. Results . FMD (at 10 μl/min, 25±3% of maximal diameter) were reduced (P<0.05) by endothelial removal (6±1%) or eNOS inhibition with N-nitro-L-arginine (L-NNA; 11±1%), but not by the specific NO scavenger 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl3-oxide (PTIO; 24±3%). Likewise, FMD was not associated with a rise in NO-associated fluorescence, while addition of PEG-catalase and silver diethyldithio-carbamate (DETC; superoxide dismutase inhibitor) reduced (P<0.05) FMD to 10±2% and 15±1%, respectively, suggestive of the implication of H 2 O 2 in FMD. Accordingly, a rise in H 2 O 2 -associated fluorescence (+133±19 a.u.) was observed simultaneously to FMD, and was reduced by L-NNA, PEG-catalase and DETC (+55±10, +64±4 and +50±10 a.u., respectively; P<0.05). Furthermore, specific inhibition of Akt by triciribine (1 μM) prevented FMD together with H 2 O 2 -associated rise in fluorescence (3±1% and +23±4 a.u., respectively, P<0.05). Triciribine, however, neither limited ACh-induced dilation nor the rise in H 2 O 2 -associated fluorescence. Conclusion . In C57Bl/6 mouse cerebral arteries, Akt-dependent activation of eNOS-derived H 2 O 2 accounts for flow-mediated dilation. This suggests a physiological role for eNOS-derived free radicals.
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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) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
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".