UCMS Causes Indiscriminate Impairment of Aortic Function in Both Lean and Obese Rats, Mediated Through a TNFα and NOX2 Dependent Pathway
Bibliographic record
Abstract
The use of unpredictable chronic mild stress (UCMS) protocols to cause stress leading to the onset of depressive like symptoms is well defined. Many studies have investigated the impact on behavior and neuronal functioning but its effect on vascular function is not well understood. Additionally, the combination of a depressive like state and metabolic syndrome (MetS) may further worsen the severity of vascular dysfunction, which is of high clinical relevance due to a high co‐prevalence. Similarly to MetS, chronic stress (UCMS) induces increases in oxidative stress, inflammation, and vascular dysfunction. Chronic stress also triggers increased sympathetic outflow and cortisol/corticosterone levels. All of these conditions can lead to impairment of endothelial function of the aorta. We have previously shown MetS impairment of aortic function is mediated, a least partially, through perivascular adipose tissue (PVAT). Adipose immune cells may play a big role in this impairment as they infiltrate the PVAT. These immune cells have the NADPH oxidase 2 (NOX2) enzyme that produces superoxides, contributing to higher oxidative stress. From previous data we know TNFαa neutralization blocks the MetS PVAT impairment and TNFα can stimulate NOX2 to produce of superoxides, which can be converted to hydrogen peroxide a more stable radical with more far reaching effects. The oxidative environment intern promotes the production of inflammatory mediators like TNFα. This highlights the interplay between inflammation and oxidative stress. The object of the current experiment was to determine the effect of UCMS with and without concomitant MetS on PVAT and PVAT regulation of aortic function. In lean rats (LZR) UCMS causes minimal effect to aortic relaxation, however relaxation (71% to 63%, p<0.05) and NO production (~40%) are impaired in the presence of PVAT. UCMS impairments appear to be caused by increased NOX2 superoxide production in PVAT and increased levels of TNFα as neutralizing TNFα or inhibiting the NOX2 enzyme resolved the PVAT mediated impairment of aortic relaxation. MetS (obese Zucker rat, OZR) alone causes significant aortic dysfunction mediated by PVAT (10% reduction of relaxation, p<0.05), which is further impaired (an additional 8%, p<0.05) by UCMS concurrent with MetS. Aortic relaxation was impaired by both, reducing sensitivity of relaxation at low doses of methacholine and reduced maximal relaxation from 64% to 50% mediated by the effect of PVAT on aortic NO production. OZR UCMS PVAT caused a significant drop in NO production below the non‐stimulated control suggesting severe endothelial dysfunction. Superoxide production (via DHE assay) was elevated in OZR UCMS. Similar to LZR, neutralizing TNFα or inhibiting the NOX2 enzyme resolved the PVAT mediated impairment. In summary UCMS causes increased superoxide production from NOX2 accompanied by increased TNFα in the PVAT. This led to impairment of aortic endothelial NO production and reduced aortic relaxation in both LZR and OZR. Support or Funding Information The authors gratefully acknowledge the support by National Institute of Health(5P20GM109098) and American Heart Association pre‐Doctoral Fellowship.
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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) | 0.000 | 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) | 0.000 | 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".