Hypoxia and ischemic stroke induce endothelial BKCa expression in cerebral arteries - a target for therapy?

Victoria Hinkley, Christian Staehr, Vladimir v Matchkov, Rajkumar Rajanathan, Yvonne Eiby, Nathan Luque, Ian J. Wright, Kirat Chand, Hong Nguyen, Nicole Jones, Shaun l Sandow, Timothy Murphy

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Expression and function of small, intermediate and large conductance calcium-activated potassium channels (S/I/BKCa) contribute to vascular tone and blood flow regulation. Arterial endothelium expresses S/IKCa, with variable expression in health vs disease. BKCa are ubiquitously expressed in vascular smooth muscle; and post-hypoxia in the endothelium of skeletal muscle arteries.
Aim: This study determines endothelial BKCa expression in the middle cerebral artery (MCA) of mouse, pig and rat. The hypotheses examined is that endothelial BKCa upregulate in MCA post-hypoxia and after ischemic stroke.
Method: Hypoxia/ischemic stroke effects were examined in newborn pig; and mouse and rat using transient mechanical and endothelin-1 occlusion of middle cerebral artery, respectively. Confocal immunohistochemistry determined the expression of protein of interest, with tissues of known distribution as controls. Functional impacts were determined in rat under normoxia, hypoxia and ischemic stroke with pressure myography and pharmacological intervention.
Results: In MCA endothelium of neonatal piglets, BKCa were expressed at a low level and increased post-hypoxia cf/ control (n = 4; P < 0.05). In adult mice and rat (n = 5–6, for each), MCA endothelial BKCa was absent under normoxia, but significantly upregulated post-hypoxia and stroke (P < 0.05). In rat MCA, iberiotoxin (IbTx; BKCa inhibitor) had no effect on vascular tone in normoxia, but increased tone post-hypoxia/stroke (n = 5–6, each; P < 0.05); suggesting no BKCa role in former, but upregulation post-hypoxia/stroke. Endothelial removal reduced MCA tone in normoxia, but significantly increased tone post-hypoxia/stroke (n = 5–6, each; P < 0.05). IbTx had no effect on MCA tone in normoxia, neither post-hypoxia/stroke (n = 5–6, each; P < 0.05). Data suggest that endothelial BKCa have no role in normoxic MCA, but regulate tone post-stroke.
Conclusions: Endothelial BKCa contribute to regulation of MCA myogenic tone after hypoxia/stroke, highlighting their potential as a target to facilitate controlled blood flow after ischemic stroke.
Original languageEnglish
Pages (from-to)S183
Number of pages1
JournalJournal of Cerebral Blood Flow and Metabolism
Volume43
Issue numberSupp. 1
DOIs
Publication statusPublished - 1 Jun 2023
Externally publishedYes

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