Capillary oxygen regulates demand–supply coupling by triggering connexin40-mediated conduction: Rethinking the metabolic hypothesis
Bibliographic record
Abstract
Coupling red blood cell (RBC) supply to O 2 demand is an intricate process requiring O 2 sensing, generation of a stimulus, and signal transduction that alters upstream arteriolar tone. Although actively debated, this process has been theorized to be induced by hypoxia and to involve activation of endothelial inwardly rectifying K + channels (K IR ) 2.1 by elevated extracellular K + to trigger conducted hyperpolarization via connexin40 (Cx40) gap junctions to upstream resistors. This concept was tested in resting healthy skeletal muscle of Cx40 −/− and endothelial K IR 2.1 −/− mice using state-of-the-art live animal imaging where the local tissue O 2 environment was manipulated using a custom gas chamber. Second-by-second capillary RBC flow responses were recorded as O 2 was altered. A stepwise drop in PO 2 at the muscle surface increased RBC supply in capillaries of control animals while elevated O 2 elicited the opposite response; capillaries were confirmed to express Cx40. The RBC flow responses were rapid and tightly coupled to O 2 ; computer simulations did not support hypoxia as a driving factor. In contrast, RBC flow responses were significantly diminished in Cx40 −/− mice. Endothelial K IR 2.1 −/− mice, on the other hand, reacted normally to O 2 changes, even when the O 2 challenge was targeted to a smaller area of tissue with fewer capillaries. Conclusively, microvascular O 2 responses depend on coordinated electrical signaling via Cx40 gap junctions, and endothelial K IR 2.1 channels do not initiate the event. These findings reconceptualize the paradigm of blood flow regulation in skeletal muscle and how O 2 triggers this process in capillaries independent of extracellular K + .
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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 | 0.001 | 0.001 |
| 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 | 0.002 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| 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".