Hypoxia and ischemic stroke modify cerebrovascular tone by upregulating endothelial BK(Ca) channels—Lessons from rat, pig, mouse, and human
Staehr, Christian, Hinkley, Victoria, Matchkov, Vladimir V., Rajanathan, Rajkumar, Hansen, Line Mathilde B., Eiby, Yvonne, Luque, Nathan, Wright, Ian, Bjorkman, Stella T., Miller, Stephanie M., Grimley, Rohan S., Dettrick, Andrew, Chand, Kirat, Nguyen, Hong L., Jones, Nicole M., Murphy, Tim V., and Sandow, Shaun L. (2025) Hypoxia and ischemic stroke modify cerebrovascular tone by upregulating endothelial BK(Ca) channels—Lessons from rat, pig, mouse, and human. Acta Physiologica, 241 (4). e70030.
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Abstract
Aim: In animal models and human cerebral arteries, the changes in endothelial cell (EC)-large conductance calcium-activated potassium channel (BK<inf>Ca</inf>) distribution, expression, and function were determined in hypoxia and ischemic stroke. The hypothesis that hypoxia and ischemic stroke induce EC-BK<inf>Ca</inf> in cerebral arteries was examined. Methods: Immunohistochemistry analyzed BK<inf>Ca</inf> 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-BK<inf>Ca</inf> 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-BK<inf>Ca</inf> 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-BK<inf>Ca</inf> 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 BK<inf>Ca</inf> 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-BK<inf>Ca</inf> contribute to the regulation of MCA tone. Identifying unique up- and downstream signaling mechanisms associated with EC-BK<inf>Ca</inf> is a potential therapeutic target to control blood flow post-hypoxia/stroke.
| Item ID: | 88205 |
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| Item Type: | Article (Research - C1) |
| ISSN: | 1748-1716 |
| Keywords: | BKCa, blood flow, endothelium, hypoxia, ion channel, stroke |
| Copyright Information: | © 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. |
| Date Deposited: | 01 Apr 2026 01:19 |
| FoR Codes: | 32 BIOMEDICAL AND CLINICAL SCIENCES > 3201 Cardiovascular medicine and haematology > 320101 Cardiology (incl. cardiovascular diseases) @ 100% |
| SEO Codes: | 20 HEALTH > 2001 Clinical health > 200105 Treatment of human diseases and conditions @ 100% |
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