Hierarchical Arrangement of Contractile Mechanisms in Resistance Arteries
Bibliographic record
Abstract
Contraction/relaxation of vascular smooth muscle cells (VSMCs) in resistance arteries tunes tissue blood flow delivery. G‐protein coupled receptors (GPCRs) are integral to set this dynamic balance and they work by controlling two general signaling pathways. The first centers on coupling between V M and cytosolic [Ca 2+ ] via L‐type Ca 2+ channels, whereas the second operates independently of voltage through Ca 2+ sensitizing mechanisms. While untested, it is presumed that agonists activate both signaling pathways with their relative contributions remaining static across a full concentration range. In contrast, we propose a hierarchical arrangement with voltage‐dependent mechanisms preceding voltage‐independent mechanisms. To define the order and relative importance of voltage‐dependent and independent signaling to GPCR‐induced constrictions, we employed a combination of functional, pharmacological, and molecular techniques. Mouse mesenteric arteries were isolated and mounted in a pressure myograph and GPCR agonists (Thromboxane A2 mimetic and Phenylephrine) were applied globally or discretely. Arterial tone increased in a concentration dependent manner, with the subsequent application of nifedipine (L‐type Ca 2+ channel blocker) attenuating these responses, particularly at the lower concentration range. The remaining voltage‐independent constriction was blocked by calphostin C, a Protein Kinase C (PKC) inhibitor. Voltage‐independent constriction was also observed when agonists were discretely applied to a small portion of the vessel such that there was not enough charge to change membrane potential. This local change was also sensitive to calphostin C pre‐treatment. Ongoing work is focused on isolating the downstream PKC targets involved in voltage‐independent constriction. Using the highly sensitive three‐step western blot approach to probe key PKC phosphorylation sites (MYPT1‐T855, ‐T697, and CPI‐17), we have found the CPI‐17 phosphorylation site to be particularly promising in enabling agonist‐induced responses. In summary, our findings indicate a hierarchical arrangement with a shift from voltage‐dependent to voltage‐independent signaling as GPCR receptors are increasingly activated. These findings have translational application as to pathobiology of cerebral vasospasm and to its effective amelioration.
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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 | 0.001 | 0.000 |
| 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".