Activation of Hypoxia‐Inducible Factor‐1 by Sphingosine‐1‐Phosphate in vascular cells
Bibliographic record
Abstract
Sphingosine‐1‐phosphate(S1P) is a bioactive phospholipid playing a key role in angiogenesis by promoting a variety of vascular cell events. Hypoxia‐inducible factor‐1(HIF‐1), a transcriptional activator of many genes essential for adaptation to lowered oxygen levels, is also a major angiogenic inducer. Interestingly, S1P and HIF‐1 are both implicated in different cardiovascular diseases and in tumor progression. Recent studies have shown that non‐hypoxic stimuli can activate HIF‐1 in oxygenated conditions. Here, we attempt to determine whether S1P can modulate the vascular activation of HIF‐1. We show that treatment of cultured vascular cells with S1P strongly increases HIF‐1α but not HIF‐2α protein levels, through VHL‐independent stabilization of HIF‐1α. Using pharmacological inhibitors we show that elevation of HIF‐1α expression occurs through the S1P2 receptor. We demonstrate, that the HIF‐1 nuclear dimer formed upon S1P stimulation, is transcriptionally active and specifically binds to hypoxia‐responsive elements. Moreover, in smooth muscle cells, S1P regulates genes via HIF‐1, since the transcripts are diminished when HIF‐1α is silenced. Our results therefore identify S1P as a potent inducer of HIF‐1. We believe that the discovery of novel activators of HIF‐1, such as S1P, and comprehension of subsequent downstream events will have a strong impact on different aspects of vascular biology. This work is supported by the Canadian Institutes of Health Research
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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) | 0.001 | 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".