Translation of sphingosine-1-phosphate-dependent regulation of myogenic tone in human resistance arteries with heart failure
Bibliographic record
Abstract
Small resistance arteries critically influence tissue perfusion, capillary integrity, total peripheral resistance and systemic blood pressure. They do this in part by adapting diameter to transmural pressure; this intrinsic property of vascular smooth muscle is called the myogenic response. Altered myogenic responses contribute to cardiovascular pathologies, including increased total peripheral resistance in heart failure. However, underlying mechanisms are poorly understood. Sphingosine-1-phosphate (S1P) is a key regulator of the myogenic response in rodents. In mice with heart failure, the myogenic response is increased due to tumour necrosis factor alpha (TNF-alpha) and cystic fibrosis transmembrane conductance regulator (CFTR)-dependent upregulation of S1P signalling. This signalling axis is a potential therapeutic target for heart failure. However, it is unknown if the same mechanisms are operational in patients. As a first step, translation of S1P signalling-dependent regulation of the myogenic response into human resistance arteries is necessary to confirm the therapeutic potential of these new microvascular mechanisms of heart failure. Mesenteric and skeletal muscle resistance arteries were collected from bowel resection and coronary artery bypass graft (CABG) patients, respectively. The presence and functional relevance of S1P signalling was assessed by pressure myography in patients with and without heart failure. Results show molecular expression of S1P signalling components and S1P signalling-dependent regulation of the myogenic response in human resistance arteries. These data also demonstrate potential vascular bed or coronary artery disease-dependent differences in S1P pathway expression and signalling. Correlational analyses do not reveal heart failure-dependent differences in the myogenic response among CABG patients. However, findings indicate that certain co-morbidities and drugs may also influence myogenic tone, meriting further investigation. Overall, this study validates the functional relevance of S1P signalling for the first time in human resistance arteries, forming a foundation for future translation of S1P-dependent mechanisms of heart failure in different patient populations.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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".