Effect of pulsatile stretch on unfolded protein response in a new model of the pulmonary hypertensive vascular wall
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Bibliographic record
Abstract
Persistent pulmonary hypertension of the newborn (PPHN) is characterized by hypoxemia and arterial remodeling. Dynamic stretch and recoil of the arterial wall during pulsation (in normal conduit arteries, stretch 20% above diastolic diameter) maintains homeostasis; a static arterial wall is associated with remodeling. PPHN is diagnosed by echocardiography as decreased pulmonary artery wall displacement during systole, causing decreased pulmonary arterial pressure acceleration time in a stiff artery. We hypothesized that a ‘normal’ amplitude of pulsatile stretch is protective against ER stress, while the loss of stretch is a trigger for hypoxia-induced stress responses. Using a novel in vitro model of pulmonary arterial myocytes subject to repetitive stretch-relaxation cycles within a normoxic or hypoxic environment, we examined the relative impact of hypoxia (pulmonary circuit during unresolved PPHN) and cyclic mechanical stretch (diminished in PPHN) on myocyte homeostasis, specifically on signaling proteins for autophagy and endoplasmic reticulum (ER) stress. Stretch induced autophagosome abundance under electron microscopy. Hypoxia, in presence or absence of pulsatile stretch, decreased unfolded protein response (UPR) hallmark BIP (GRP78) in contractile phenotype pulmonary arterial myocytes. Inositol requiring enzyme-1 α (IRE1α) was not activated; but hypoxia induced eif2α phosphorylation, increasing expression of ATF4 (activating transcription factor-4). This was sensitive to inhibition by autophagy inhibitor bafilomycin A1. We conclude that in the pulmonary circuit, hypoxia induces one arm of the UPR pathway and causes ER stress. Pulsatile stretch ameliorates the hypoxic UPR response, and while increasing presence of autophagosomes, does not activate canonical autophagy signaling pathways. We propose that simultaneous application of hypoxia and graded levels of cyclic stretch can be used to distinguish myocyte signaling in the deformable pulmonary artery of early PPHN, versus the inflexible late stage PPHN artery.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 it