Hypoxia and ischemic stroke modify cerebrovascular tone by upregulating endothelial BK(Ca) channels—Lessons from rat, pig, mouse, and human

Christian Staehr; Victoria Hinkley; Vladimir Matchkov; Rajkumar Rajanathan; Line  Mathilde B Hansen; Yvonne Eiby; Nathan Luque; Ian Wright; Stella T Bjorkman; Stephanie M Miller; Rohan S Grimley; Andrew Dettrick; Kirat Chand; Hong L Nguyen; Nicole M Jones; Tim V Murphy; Shaun Sandow

doi:10.1111/apha.70030

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Hypoxia and ischemic stroke modify cerebrovascular tone by upregulating endothelial BK(Ca) channels—Lessons from rat, pig, mouse, and human

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Hypoxia and ischemic stroke modify cerebrovascular tone by upregulating endothelial BK(Ca) channels—Lessons from rat, pig, mouse, and human

Christian Staehr, Victoria Hinkley, Vladimir Matchkov, Rajkumar Rajanathan, Line Mathilde B Hansen, Yvonne Eiby, Nathan Luque, Ian Wright, Stella T Bjorkman, Stephanie M Miller, …

Acta Physiologica, Vol.241(4), pp.1-12

2025

DOI: https://doi.org/10.1111/apha.70030

PMCID: PMC11926774

PMID: 40116175

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Abstract

Medical physiology

BKca

blood flow

endothelium

hypoxia

ion channel

stroke

Aim In animal models and human cerebral arteries, the changes in endothelial cell (EC)-large conductance calcium-activated potassium channel (BKCa) distribution, expression, and function were determined in hypoxia and ischemic stroke. The hypothesis that hypoxia and ischemic stroke induce EC-BKCa in cerebral arteries was examined. Methods Immunohistochemistry analyzed BKCa expression in EC and smooth muscle (SM) of the middle-cerebral artery (MCA) from rat, piglet, and mouse, and pial arteriole of human. Pressure myography with pharmacological intervention characterized EC-BKCa and TRPV4 function in rat MCA. Electron microscopy determined caveolae density and vessel properties in rat and mouse MCA. Results In rat, pig, and human cerebral vessels, EC-BKCa was absent in normoxia; present after chronic (rat) and acute hypoxia (pig), post-ischemic stroke in human vessels, and after endothelin-1-induced stroke in rats. Mouse MCA EC-BKCa expression increased after acute hypoxia. In rat MCA post-hypoxia and stroke, EC and SMC caveolae density increased, with reduced medial thickness, and unchanged diameter. Caveolae and BKCa did not colocalize. In rat MCA, iberiotoxin (IbTx) potentiated pressure-induced tone in hypoxia/stroke, but not in normoxia. In normoxia, overall MCA tone was unaffected by endothelial removal, but was increased in hypoxia/stroke, where there was no additive effect of endothelial removal and IbTx on tone. Functional TRPV4 was expressed in EC of rat MCA post-stroke. Conclusions In post-hypoxia/stroke, but not in normoxia, EC-BKCa contribute to the regulation of MCA tone. Identifying unique up- and downstream signaling mechanisms associated with EC-BKCa is a potential therapeutic target to control blood flow post-hypoxia/stroke.

Details

Title: Hypoxia and ischemic stroke modify cerebrovascular tone by upregulating endothelial BK(Ca) channels—Lessons from rat, pig, mouse, and human
Authors: Christian Staehr (Corresponding Author) - Aarhus University
Victoria Hinkley - University of the Sunshine Coast, Queensland, School of Health - Biomedicine
Vladimir Matchkov - Aarhus University
Rajkumar Rajanathan - Aarhus University
Line Mathilde B Hansen - Aarhus University
Yvonne Eiby - The University of Queensland
Nathan Luque - UNSW Sydney
Ian Wright - James Cook University
Stella T Bjorkman - The University of Queensland
Stephanie M Miller - The University of Queensland
Rohan S Grimley - Griffith University
Andrew Dettrick - Sunshine Coast University Hospital
Kirat Chand - The University of Queensland
Hong L Nguyen - UNSW Sydney
Nicole M Jones - UNSW Sydney
Tim V Murphy - UNSW Sydney
Shaun Sandow - University of the Sunshine Coast, Queensland, School of Health - Biomedicine
Publication details: Acta Physiologica, Vol.241(4), pp.1-12
Publisher: Wiley-Blackwell Publishing Ltd.
Date published: 2025
DOI: 10.1111/apha.70030
ISSN: 1748-1716
PMID: 40116175; PMC11926774
Copyright note: © 2025 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Data Availability: The data that support the findings of this study are available from the corresponding author upon reasonable request.
Grant note: Work was supported by the Brain Foundation (Australia), the University of the Sunshine Coast SPARK fund to S.L.S.; Lundbeck Foundation R344-2020-952, R412-2022-449, and Independent Research Fund Denmark 8020-00084B to V.V.M.; and Riisfort, Knud Højgaard's, Helga & Peter Korning's (472123-006 #55), Augustinus (#21-2471), and Dagmar Marshall Foundations, Danish Cardiovascular Academy (PDC5-2024004-DCA; funded by the Novo Nordisk Foundation, grant number NNF20SA0067242, and the Danish Heart Foundation), and Gerhard Brønsted's travel grant to C.S.
Organisation Unit: School of Health - Biomedicine; Healthy Ageing Research Cluster; School of Health; Cancer Research Cluster
Language: English
Record Identifier: 991113052002621
Output Type: Journal article

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