Abstract 4920: Endothelial-Targeted BMPR2 Loss-of-Function Mutations Cause Increased Apoptosis and Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Introduction: Pulmonary arterial hypertension (PAH) is a rare and fatal disease caused by excessive remodelling of small pulmonary arterioles. Heterozygous loss-of-function mutations in the bone morphogenetic protein receptor 2 (BMPR2) have recently been implicated in patients with familial and idiopathic PAH. However, how mutations in this ubiquitously expressed receptor result in a specific abnormality of the lung microcirculation is unknown. We hypothesized that mutations in BMPR2 lead to PAH by increasing the susceptibility of ECs to apoptosis, particularly within fragile pulmonary arterioles. Aims: To examine the effect of endothelial targeted overexpression of a BMPR2 deletional mutation on EC apoptosis, pulmonary hemodynamics and arteriolar remodelling. Methods: We developed an endothelial-specific binary transgenic (BT) mouse model in which the driver mice express the tetracycline transactivator under the control of the endothelial-restricted V-cadherin promoter and the responder mice harbour a BMPR2 transgene containing an arginine-to-stop mutation in the receptor’s C-terminal domain driven by a tetracycline responsive promoter. Pulmonary artery pressure was evaluated by measuring right ventricular systolic pressure (RVSP). Fluorescent microangiography (FMA) was performed to visualize the 3D architecture of the pulmonary microcirculation. Results: RVSP was significantly increased in BT mice compared to non binary controls (p < 0.05; n = 9), associated with increased muscularization of small pulmonary arterioles detected by α -smooth muscle actin immunostaining. In addition, FMA revealed decreased perfusion and distal pre-capillary discontinuity in BT mice. TUNEL staining also demonstrated a significant increase in the number of apoptotic cells in BT mice compared to non binary controls (5.8 ± 1.1, 1.0 ± 0.7 positive cells/HPF, respectively; p < 0.05; n = 4). Conclusions: These data suggest that BMPR2 mutations increase the susceptibility to apoptosis, possibly leading to EC loss and pre-capillary arteriolar discontinuity. This new model will help elucidate the pathophysiological events leading to the development of PAH and provide a unique tool to evaluate novel potential treatments for this disease.
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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 | 0.000 |
| 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
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".