Acta physiologica (Oxford, England) · 2025
Hypoxia and ischemic stroke modify cerebrovascular tone by upregulating endothelial BK(Ca) channels-Lessons from rat, pig, mouse, and human.
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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, Sandow Shaun L
Аннотация
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.
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.