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Capillary oxygen regulates demand-supply coupling by triggering connexin40-mediated conduction5.89 MB
Published VersionCC BY-NC-ND V4.0, Open Access
Journal article
Capillary oxygen regulates demand-supply coupling by triggering connexin40-mediated conduction: Rethinking the metabolic hypothesis
National Academy of Sciences. Proceedings, Vol.121(8), pp.1-12
2024
PMID: 38349880
Abstract
Coupling red blood cell (RBC) supply to O2 demand is an intricate process requiring O2 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 (KIR) 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 KIR2.1−/− mice using state-of-the-art live animal imaging where the local tissue O2 environment was manipulated using a custom gas chamber. Second-by-second capillary RBC flow responses were recorded as O2 was altered. A stepwise drop in PO2 at the muscle surface increased RBC supply in capillaries of control animals while elevated O2 elicited the opposite response; capillaries were confirmed to express Cx40. The RBC flow responses were rapid and tightly coupled to O2; computer simulations did not support hypoxia as a driving factor. In contrast, RBC flow responses were significantly diminished in Cx40−/− mice. Endothelial KIR2.1−/− mice, on the other hand, reacted normally to O2 changes, even when the O2 challenge was targeted to a smaller area of tissue with fewer capillaries. Conclusively, microvascular O2 responses depend on coordinated electrical signaling via Cx40 gap junctions, and endothelial KIR2.1 channels do not initiate the event. These findings reconceptualize the paradigm of blood flow regulation in skeletal muscle and how O2 triggers this process in capillaries independent of extracellular K+.
Details
- Title
- Capillary oxygen regulates demand-supply coupling by triggering connexin40-mediated conduction: Rethinking the metabolic hypothesis
- Authors
- Paulina M Kowalewska (Corresponding Author) - University of Western OntarioStephanie L Milkovich (Author) - University of Western OntarioDaniel Goldman (Author) - University of Western OntarioShaun L Sandow (Author) - University of the Sunshine Coast, Queensland, School of Health - BiomedicineChristopher G Ellis (Author) - University of Western OntarioDonald G Welsh (Author) - University of Western Ontario
- Publication details
- National Academy of Sciences. Proceedings, Vol.121(8), pp.1-12
- Publisher
- National Academy of Sciences
- Date published
- 2024
- DOI
- 10.1073/pnas.2303119121
- ISSN
- 1091-6490; 0027-8424
- PMID
- 38349880
- Copyright note
- © 2024 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
- Data Availability
- Data that support the findings of this study are provided within this article and supplemental file.
- Grant note
- 453253 / Gouvernement du Canada | Canadian Institutes of Health Research (IRSC)
- Organisation Unit
- School of Health - Biomedicine; Healthy Ageing Research Cluster
- Language
- English
- Record Identifier
- 991000994602621
- Output Type
- Journal article
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