Focal cerebral ischemic stroke results in endothelial BKCa expression and altered function, with no change in TRPV4 function, in middle cerebral artery

Large conductance calcium-activated potassium channels (BKCa) are absent in healthy intact artery endothelium, but have a stress-induced expression following chronic hypoxia and cell isolation/culture. BKCa can form complexes with transient receptor potential vanilloid type 4 channels (TRPV4) that are implicated in control of vessel tone and in some models, stroke etiology. Confocal-immunohistochemistry determined BKCa-alpha and -beta1, and TRPV4 distribution in adult male SD rat middle cerebral artery (MCA) in acute endothelin-induced stroke and chronic hypoxia; and hypoxia following stroke, and in human cerebral pial arterioles from terminal cerebral stroke and control subjects. MCA pressure myography and BKCa and TRPV4 activators and blockers determined channel function. BKCa-alpha and -beta1 were absent in endothelium of MCA from untreated and saline-treated control rats, but present in stroke, hypoxia and hypoxia following stroke. Smooth muscle BKCa-alpha and -beta1 were present in control and upregulated in stroke, hypoxia and hypoxia following stroke. Endothelial TRPV4 were present in control and upregulated in stroke and hypoxia, but unchanged in hypoxia following stroke. Smooth muscle TRPV4 were present in control, and unchanged in hypoxia; with reduced expression in stroke and hypoxia following stroke. Endothelial BKCa-alpha was absent in control human pial arterioles, present in stroke; and upregulated in smooth muscle of stroke. In rat MCA, basal BKCa regulating myogenic tone is increased in stroke; whereas TRPV4 function is unchanged. Intact MCA endothelium can be induced to express functional BKCa, and thus targeting of BKCa and its related signaling pathways is a rational approach to correct altered cerebral perfusion.