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

AIM

In animal models and human cerebral arteries, the changes in endothelial cell (EC)-large conductance calcium-activated potassium channel (BK) distribution, expression, and function were determined in hypoxia and ischemic stroke. The hypothesis that hypoxia and ischemic stroke induce EC-BK in cerebral arteries was examined.

METHODS

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