Functional Bias of Contractile Control in Mouse Resistance Arteries
Bibliographic record
Abstract
Abstract Background Constrictor agonists set vascular tone through two coupling processes, one tied to (electromechanical), the other independent (pharmacomechanical) of membrane potential (V M ). This arrangement raises an intriguing query: are they variably recruited such that each agonist elicits a range of vasomotor signatures, functionally biased towards one mechanism or the other? This query underlies this study and our examination of agonist-induced arterial constriction. Methods Mouse mesenteric arteries were exposed to a classic G q/11 (phenylephrine) or G q/11 /G 12/13 (U46619) coupled receptor agonist, and responses monitored in the absence and presence of L-type Ca 2+ channel/protein kinase inhibitors. Contractile work was supplemented with measures of protein phosphorylation, V M , and cytosolic Ca 2+ ; conceptual insights were enhanced with computational modeling. Results Each constrictor elicited a response curve that was attenuated and rightward shifted by nifedipine, findings aligned with functional bias; electromechanical coupling preceded pharmacomechanical, the latter’s importance rising with agonist concentration. Ensuing contractile and phosphorylation (CPI-17 & MYPT1 (T-855 & T-697)) measures revealed phenylephrine-induced pharmacomechanical coupling was tied to protein kinase C (PKC), while U46619 was tied to both PKC and Rho-kinase. A switch to pharmacomechanical coupling dominance occurred when agonist superfusion was replaced with discrete application to a small portion of artery. This switch was predicted by electromechanical modeling and supported by direct measures of V M and cytosolic Ca 2+ . Conclusions Our work illustrates that constrictor agonists elicit functionally biased responses and that arteries toggle among contractile mechanisms, dependent on receptor signal bias, structural/electrical properties, and how agents are applied. We discuss how hemodynamic control is intimately tied to functional bias in both health and disease states, including but not limited to arterial vasospasm. Highlights Agonist-induced constrictor responses exhibit a “functional bias” toward electromechanical or pharmacomechanical coupling dependent on agent concentration and mode of application. Electromechanical coupling typically but not exclusively precedes pharmacomechanical, the latter rising to prominence with agent concentration. Pharmacomechanical coupling is mediated through receptor pathways linked to PKC and Rho-kinase, regulatory proteins that target the catalytic and targeting subunit of MLCP. Functional bias is malleable and thus each agonist elicits a range of vasomotor signatures, each presumptively important in controlling blood flow delivery in space and time.
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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".