TY - JOUR
T1 - Hypoxia and ischemic stroke modify cerebrovascular tone by upregulating endothelial BK(Ca) channels—Lessons from rat, pig, mouse, and human
AU - Staehr, Christian
AU - Hinkley, Victoria
AU - Matchkov, Vladimir V.
AU - Rajanathan, Rajkumar
AU - Hansen, Line Mathilde B.
AU - Eiby, Yvonne
AU - Luque, Nathan
AU - Wright, Ian
AU - Bjorkman, Stella T.
AU - Miller, Stephanie M.
AU - Grimley, Rohan S.
AU - Dettrick, Andrew
AU - Chand, Kirat
AU - Nguyen, Hong L.
AU - Jones, Nicole M.
AU - Murphy, Tim V.
AU - Sandow, Shaun L.
N1 - Publisher Copyright:
© 2025 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.
PY - 2025/4
Y1 - 2025/4
N2 - 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.
AB - 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.
KW - BK
KW - blood flow
KW - endothelium
KW - hypoxia
KW - ion channel
KW - stroke
UR - http://www.scopus.com/inward/record.url?scp=105000842643&partnerID=8YFLogxK
U2 - 10.1111/apha.70030
DO - 10.1111/apha.70030
M3 - Article
AN - SCOPUS:105000842643
SN - 1748-1708
VL - 241
JO - Acta Physiologica
JF - Acta Physiologica
IS - 4
M1 - e70030
ER -
