PAR2, not PAR1, regulates endothelium‐dependent vascular tone in resistance arteries
Bibliographic record
Abstract
Protease activated receptors (PARs), a subfamily of G‐protein‐coupled receptors, are activated by cleavage of its extracellular domains. Four mammalian PAR members have been identified (PAR1‐4). PAR1 is the thrombin receptor, while PAR2 is activated physiologically by peptides or N‐terminal proteolytic cleavage. The resulting cleaved N‐termini acts as a tethered ligand that initiates receptor signaling. PARs may regulate vascular tone, cell permeability and cell proliferation. However, the precise roles of PAR1 and PAR2 in regulating vascular tone via the endothelium, and how PAR‐evoked signals transmit extracellularly and intracellularly, are incompletely understood. To explore the physiological functions, and the underlying signalling pathways in native endothelium, PAR1 (TFLLR‐NH 2 ) and PAR2 (2‐Furoyl‐LIGRLO‐amide; 2fLI) activating peptides were used, and changes in intracellular Ca 2+ and contractility measured in en face rat mesenteric arteries. Surprisingly, PAR1 activation (TFLLR‐NH 2 or trypsin) neither triggered Ca 2+ signals in endothelial cells or alter vascular tone. On the other hand, PAR2 activation (2fLI) evoked large global propagating Ca 2+ waves in endothelial cells and endothelium‐dependent dilation of mesenteric arteries. The Ca 2+ signals evoked by PAR2 activation were kinetically distinctive when compared to those of muscarinic receptor activation. PAR2 activation (2fLI) also evoked responses in different clusters of endothelial cells from those of muscarinic receptor (acetylcholine) activation. PAR2 activation with 2fLI or trypsin failed to evoke Ca 2+ signals after depletion of the internal store with the Ca 2+ ‐ATPase (SERCA) inhibitor, CPA. This result suggests that PAR2 evokes Ca 2+ release from internal stores. Pharmacological block of inositol 1,4,5‐trisphosphate (IP 3 ) with either 2‐APB or caffeine, also blocked PAR2‐evoked Ca 2+ signals. Phospholipase C inhibition (U73122) also blocked the Ca 2+ signals evoked by PAR2 activation. Therefore, PAR2 is a PLC linked G protein coupled receptor which evokes Ca 2+ release from the internal store via IP 3 receptors in endothelial cells. The TRPC3 blocker, PYR3 and store‐operated Ca 2+ entry (SOCE) blocker, YM58483 each significantly supressed PAR2 mediated Ca 2+ signals, suggesting internal store was replenished via TRPC3 channel and SOCE. In conclusion, PAR2 rather than PAR1, regulates vascular tone in mesenteric arteries by evoking Ca 2+ release from the internal store via IP 3 receptors to generate propagating Ca 2+ waves in distinct sub‐populations of endothelial cells.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".