Cholesterol: A Novel Regulator of Vasoreactivity in Pulmonary Arteries
Bibliographic record
Abstract
Cholesterol: A Novel Regulator of Vasoreactivity in Pulmonary ArteriesChronic hypoxia (CH) causes Ca 21 sensitization in pulmonary artery smooth muscle cells (PASMCs), thus augmenting pulmonary artery vasoconstrictor responses (1).Although increased vasoreactivity is considered to contribute to the development of pulmonary hypertension (PH), the exact mechanism of Ca 21 sensitization remains unresolved.In this issue of the Journal, Norton and colleagues (pp.709-718) report on studies testing whether alterations in lipid domains of smooth muscle cells may contribute to increased pulmonary artery vasoreactivity in CH (2).This hypothesis was fueled by the authors' previous finding that increased Ca 21 sensitization in CH is mediated via EGFR (epidermal growth factor receptor)-dependent NOX2 (NADPH oxidase 2) activation and subsequent superoxide-regulated ROCK (Rho-associated protein kinase) activation (3).Importantly, both EGFR and NOX2 can be regulated by Cav-1 (caveolin-1) (4, 5), the eponymous structural protein of the 50-to 80-nm V-shaped cholesterol-rich invaginations of the plasma membrane termed caveolae.Cav-1 also controls local cholesterol content and acts as regulatory scaffold protein for various signaling molecules, resulting in the compartmentalization of vasoregulatory signaling molecules and ion channels, including eNOS (endothelial nitric oxide synthase), TRPC6 (transient receptor potential channel 6), and transient receptor potential vanilloid 4 in caveolae (6, 7).Consistent with an important role for Cav-1 in PH, preclinical studies showed increased pulmonary vascular resistance in Cav1deficient mice (8), and whole-exome sequencing identified an association of CAV1 with human PH disease (9).In intrapulmonary arteries isolated from CH and control rats, Norton and colleagues did not detect any significant changes in overall Cav-1 content or number of caveolae per cell membrane length of PASMCs.Interestingly, however, the authors detected a distinct loss of z50% in membrane cholesterol in the medial layer of intrapulmonary arteries in CH rats compared with control rats.This finding is in line with previous reports documenting reduced cholesterol levels in hypoxia due to a degradation of the ratecontrolling enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (10).To test for the functional relevance of cholesterol depletion, the authors repleted cholesterol in isolated pressurized arteries, which normalized the vasoconstrictive response to depolarization in pulmonary arteries of CH rats but had no effect in control rats.These experiments were conducted in Ca 21 -permeabilized and endothelium-disrupted arteries, thus excluding changes in Ca 21 influx or release, or endothelial-mediated tone regulation.Rather, these findings identify changes in cholesterol as a cause of Ca 21 sensitization in CH pulmonary arteries.Conversely, however, cholesterol depletion of control pulmonary arteries by methyl-bcyclodextrin to a similar extent as in CH pulmonary arteries did
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How this classification was reachedexpand
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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".