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

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica Pub Date : 2025-03-21 DOI:10.1111/apha.70030

Christian Staehr, Victoria Hinkley, Vladimir V. 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 L. Sandow

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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_Ca) distribution, expression, and function were determined in hypoxia and ischemic stroke. The hypothesis that hypoxia and ischemic stroke induce EC-BK_Ca in cerebral arteries was examined.

Methods

Immunohistochemistry analyzed BK_Ca 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_Ca 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_Ca 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_Ca 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_Ca 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_Ca contribute to the regulation of MCA tone. Identifying unique up- and downstream signaling mechanisms associated with EC-BK_Ca is a potential therapeutic target to control blood flow post-hypoxia/stroke.

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来源期刊

Acta Physiologica 医学-生理学

CiteScore

11.80

自引率

15.90%

发文量

182

审稿时长

4-8 weeks

期刊介绍： Acta Physiologica is an important forum for the publication of high quality original research in physiology and related areas by authors from all over the world. Acta Physiologica is a leading journal in human/translational physiology while promoting all aspects of the science of physiology. The journal publishes full length original articles on important new observations as well as reviews and commentaries.