Role of apoptosis in persistent regression of structurally-based vascular resistance following inhibition of angiotensin II
Bibliographic record
Abstract
It has been previously shown that long-term RAS inhibition induces regression of vascular structure and a reduction in MAP, both of which persist long after treatment is stopped. While the mechanism for these changes has not been fully elucidated, both apoptosis and rearrangement of VSMCs has been implicated in the resulting decrease in media and increase in lumen diameter. The present study examines the impact of short-term RAS inhibition on MAP, structurally-based vascular resistance and susceptibility to apoptosis during and/or after withdrawal of treatment. SHR were treated with enalapril or losartan (E, L=30 mg/kg per day, p.o, 7 or 14 days). MAP was continuously monitored via radiotelemetry. Structurally-based vascular resistance was assessed by hindlimb perfusion (Dextran-Tyrodes) at the end of treatment or 2wks after drug withdrawal. The hindlimb vascular properties assessed included: resistance at max dil (MD=lumen size) and at max con (MC=medial bulk). After 7 days of treatment, aortic and mesenteric vessels were excised, cleaned then incubated in Tyrodes (37°C, 1% O2, 6hrs). DNA was extracted (phenol : chloroform) and apoptosis was detected via DNA fragmentation. E and L induced similar reduction in off-treatment level of MAP (E: -12±2.3%, L: -12±5.0%). Further, a similar regression of medial bulk was induced following 7 (MC: E: -12±5.9%, L: -12±6.6%) and 14 (MC: E: -12±2.7%, L: -12±6.1%) days of treatment, with no impact on lumen. In contrast, 2wks after stopping enalapril treatment both indices of vascular structure were similarly changed: medial index (MC: -12±8.0%) and lumen (MD: -15±7.9%). DNA fragmentation response in aortic and mesenteric vessels revealed that 7 days of E or L treatment did not change the susceptibility to hypoxia-induced apoptosis. A major finding of the present study is that only 2 wks of RAS inhibition is required to induce persistent changes in MAP and structurally-based vascular resistance. In addition, given the discordance between changes in vascular media and lumen during the on and off-treatment period, the vascular structural remodeling appears to continue even in the absence of drug therapy. We have previously shown that hypoxia is an effective stimulus to determine susceptibility to cell death. The present findings demonstrate that although short-term RAS inhibition induces some vascular remodeling, this action is not associated with significant changes in the susceptibility of VSMC to induced apoptosis. These findings may suggest a lesser role for apoptosis in the mechanism of persistent changes in vascular structure than has been previously hypothesized.
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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".