Endothelial Inwardly Rectifying K+ Channel Subunit 2.1 Critically Enables Flow‐mediated Dilation in Cerebral Resistance Arteries

Abstract

Cerebral blood flow is a highly regulated process tied to the expression of ion channels in endothelial and smooth muscle cells. Of particular note are endothelial inwardly rectifying K+ channels (KIR), membrane proteins that presumably sense hemodynamic stimuli such as blood flow. This study sought to clearly define the role of endothelial KIR2.1 in cerebral arterial blood flow sensing using floxed control and endothelial KIR2.1‐/‐ mice. Experiments progressed from single cell (patch‐clamp electrophysiology of cerebral endothelial and smooth muscle), to isolated vessel (myography of cerebral resistance arteries) and finally to intact organism (arterial spin‐labeling magnetic resonance imaging). Electrophysiological analysis confirmed the presence of KIR activity in endothelial cells from floxed but not endothelial KIR2.1‐/‐ mice; the former was subsequently shown to be flow sensitive. Smooth muscle KIR activity was comparable among the two animal groups. Vessel experiments next revealed that flow‐induced vasodilation was diminished in endothelial KIR2.1‐/‐ mice. In the absence of endothelium, Ba2+‐induced constriction was comparable among the two groups consistent with preserved smooth muscle KIR activity. Intriguingly, the diminishment of cellular and tissue level responses in endothelial KIR2.1‐/‐ mice did not lead to apparent cerebral flow abnormalities (cortex, cerebral nuclei, hippocampus, thalamus, hypothalamus and midbrain), at baseline or following a systemic blood pressure challenge (intraperitoneal phenylephrine). These findings underscore a role for endothelial KIR2.1 activity in hemodynamic sensing, one that is subtle and dynamically balanced with other mechanisms that set cerebral arterial blood flow.