Pannexin 1 – a novel regulator of hypoxic pulmonary vasoconstriction
Bibliographic record
Abstract
Hypoxic pulmonary vasoconstriction (HPV) is a physiological response to alveolar hypoxia by which pulmonary blood flow is redirected from poorly ventilated areas to better aerated lung regions. Sustained HPV plays a critical role in the development of pulmonary hypertension (PH) but the exact signaling pathways underlying HPV remain incompletely defined. Recently, ATP release via Pannexin 1 (Panx1) and subsequent purinergic signaling have been linked to transient receptor potential vanlloid 4 (TRPV4) channel mediated Ca 2+ signaling in systemic vasoconstriction. Here, we probed for a similar role of Panx1 in HPV and the development of PH. To test the role of Panx1, we measured HPV as increase in pulmonary artery pressure (PAP) in response to hypoxia in lungs of endothelial cell (Cdh5‐CreERT2/Panx1 fl/fl ) and smooth muscle cell specific (SMMHC‐CreERT2/Panx1 fl/fl ) Panx1‐KO mice. Isolated perfused lungs (IPL) of C57Bl6/J and Panx1‐deficient mice were ventilated with normoxic (20% O 2 ; 5% CO 2 , 75% N 2 ) or hypoxic gas (1% O 2 ; 5% CO 2 , 94% N 2 ) and PAP was recorded via a pulmonary artery catheter. To elucidate the role of Panx1 in the development of PH, C57Bl6/J as well as Panx1‐KO mice were kept under hypoxic conditions (10% O 2 ) for 5 weeks followed by measurement of right ventricular systolic pressure, echocardiography and histology. Panx1 protein was expressed in human pulmonary artery endothelial cells as well as in human pulmonary artery smooth muscle cells (hPASMCs). Genetic deletion of Panx1 in smooth muscle cells, yet not in endothelial cells reduced the HPV response in isolated mouse lungs. In lungs of C57Bl6/J mice, Panx1‐inhibition by the non‐specific Panx1 inhibitors spironolactone or probenecid and the Panx1 specific inhibitory peptide ( 10 Panx1) effectively attenuated HPV. Yet, genetic deletion of Panx1 in either endothelial or smooth muscle cells did not prevent the development of PH in mice. Interestingly, ATP release in response to hypoxia was not detectable in PASMC, and ATP degradation as well as inhibition of purinergic receptors failed to affect HPV. Rather, TRPV4 antagonism and Panx1 inhibition inhibited the hypoxia‐induced increase of intracellular Ca 2+ concentration ([Ca 2+ ] i ) in PASMC in an additive manner, suggesting that Panx1 regulates [Ca 2+ ] i independently of the ATP‐P2Y‐TRPV4 signaling axis. In line with this notion, Panx1 overexpression increased the [Ca 2+ ] i response to hypoxia in HeLa cells. Here we identify Panx1 as novel regulator of HPV. The role of Panx1 in HPV was, however, not attributable to ATP release and downstream purinergic receptor signaling or TRPV4 activation, but may involve a direct role of Panx1 as Ca 2+ channel. In contrast to its role in HPV, Panx1 does not seem to contribute to chronic hypoxic PH.
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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 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".