Abstract 375: A New Mouse Model to Characterize the Mechanisms of Endothelin-1-Induced Vascular Injury
Bibliographic record
Abstract
Objective: To develop a model permitting the study of the mechanisms of endothelin (ET-1)-induced vascular injury, we generated an inducible and endothelial cell (EC)-restricted human ET-1 ( EDN1 ) cDNA overexpressing transgenic mouse, which would accordingly be devoid of developmental effects. Methods and Results: A transgene was engineered that expresses chloramphenicol acetyltransferase ( cat ) cDNA prior to Cre-mediated excision, and EDN1 cDNA after Cre-mediated excision, under the control of cytomegalovirus immediate early enhancer/chicken β-actin promoter (CAG). Co-transfection of Cre expression vector and pCAG- cat - EDN1 caused a 30-fold increase in ET-1 production evaluated by ELISA. A DNA fragment containing the CAG- cat - EDN1 transgene was used to generate transgenic mice. PCR genotyping demonstrated that 14/132 mice were transgenic. Two of 7 transgenic lines were selected based on cardiac cat expression level, which were twice higher in line C-134 than C-170. Inducible EC-restricted EDN1 mice were generated crossing CAG- cat - EDN1 mice with mice expressing Cre recombinase fused to a tamoxifen (TAM)-inducible modified estrogen receptor ligand binding domain ( Cre ER T2 ) under control of EC-specific receptor tyrosine kinase ( Tie2 ) promoter. To investigate the extent of CreER T2 activation by TAM and tissue specificity, Tie2 -CreER T2 mice were crossed with ROSA mT-mG/mT-mG reporter mice expressing a membrane-targeted tandem dimer tomato (mT) before Cre-mediated excision, and membrane-targeted enhanced green fluorescent protein (mG) after excision. Tie2 -CreER T2 / cat - EDN1 and Tie2 -CreER T2 / ROSA mT-mG/+ mice were treated with 1 mg TAM/d SC for 5 d and sacrificed 14-16 d later. mG expression was detected in 22±3% of mesenteric artery EC of Tie2 -CreER T2 / ROSA mT-mG/+ mice. Plasma ET-1 levels were similar in vehicle-treated Tie2 -CreER T2 / cat - EDN1 (1.2±0.1 pg/mL, n=4) and wild-type mice (1.1±0.1 pg/mL, n=2), demonstrating no leaky expression. TAM induced 8-fold increase in plasma ET-1 levels in Tie2 -CreER T2 / cat - EDN1 mice (9.1 ± 0.3 pg/mL, n = 4). Conclusion: Tie2 -CreER T2 / cat - EDN1 -inducible EC-restricted EDN1 overexpressing mice allow the study of ET-1 vascular effects in adult independently of developmental effects.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.003 |
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".