Abstract 16647: Loss of Reversibility in Flow-Induced Pulmonary Arterial Hypertension is Associated With a Senescent Vascular Phenotype and Can Be Rescued by Targeted Senolysis
Bibliographic record
Abstract
Introduction: Patients with congenital heart disease (CHD) are at risk of developing progressive pulmonary arterial hypertension (PAH). Timely hemodynamic unloading (HU) by surgical shunt correction usually reverses the arteriopathy, but the timepoint when or reason why PAH becomes irreversible remains elusive. Methods: PAH was created in syngeneic rats by monocrotalin (MCT) injection and an aorto-caval shunt. For HU at different PAH stages, the left donor lung with PAH was transplanted into healthy recipients at t14/t21/t28. Recipients were sacrificed 21days after transplantation. Results: MCT+Shunt induced medial neomuscularization from t14, and neointimal lesions from t21, causing arteriolar occlusion and PAH. HU normalized the vascular morphology in all t14 rats and in 7/10 t21 rats, whereas no reversal or progressive occlusion occurred in 3/10 t21 and all t28 rats. RNA-sequencing revealed that activated pro-proliferative/regenerative, pro-apoptotic and DNA-repair pathways were associated with reversal after HU. This was confirmed immunohistochemically by increased vascular-specific Ki67, Caspase3 and Rad51 protein expression. In contrast, irreversibility was associated with deactivation of latter pathways and activated pro-survival, pro-senescence and pro-inflammatory pathways, as confirmed by increased Survivin, p16 ink4A , p21 cip1 , TNFα, IL6 and MMP2. These findings were also confirmed in human PAH-CHD explant tissue. Finally, we report that the senolytic BCL2 antagonist ABT263 selectively targets rat endothelial cells made senescent by irradiation. Moreover, low-dose ABT263 treatment from t25 to t32 in MCT+Shunt rats significantly improved pulmonary hemodynamics and relieved PAH symptoms. Conclusions: Similar to clinical observations in PAH-CHD, this study showed that HU reverses PAH only in an early stage, and describes a zone of no return. We characterized the mechanistic basis for (loss of) reversibility, showing a distinct switch from increased proliferation/regeneration, apoptosis and DNA-repair, to a growth arrested, apoptosis-resistant and intrinsically pro-inflammatory phenotype, suggesting a role for senescence. Reversal of this phenotype by targeted senolysis also reversed PAH beyond the zone of no return.
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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) | 0.007 | 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".