Transgenic mice overexpressing an endothelial‐targeted Fas‐inducing apoptosis construct exhibit pulmonary hypertension associated with marked lung arterial remodeling
Bibliographic record
Abstract
Objective Pulmonary arterial hypertension (PAH) is a lethal disease, characterized by complex vascular lesions and increased pulmonary vascular resistance. To test the hypothesis that lung EC apoptosis at the level of distal pulmonary arterioles is necessary and sufficient to cause PAH phenotype we developed a novel transgenic model. Methods and Results The F as‐ I nduced A poptosis (FIA) construct was expressed under the control of e ndothelial‐specific, Tie2 promoter in transgenic mice (i.e. EFIA mice). Two transgenic lines characterized by low and high expression levels (LE and HE, respectively) were generated. LE‐EFIA exhibited normal pulmonary hemodynamics and vascular structure at baseline; however, administration of a small molecule dimerizing agent, AP20187, resulted in lung microvascular apotosis and modest dose‐dependent increase in RVSP. Interestingly, HE‐EFIA transgenic mice showed significant elevation in baseline RVSP compared to wild‐type controls even in the absence of the AP compound (34± vs. 24±4 mm Hg, respectively; p<0.005). 40% of HE‐EFIA mice also exhibited perivascular lesions, localized to distal lung arterioles which were highly proliferative by Ki67 and EDU staining, and exhibited variable degrees of apoptosis. Conclusion Our data suggest that EC apoptosis is sufficient to induce PAH, which is associated with marked inflammation and remodeling of lung arterioles.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".