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(Circulation Research. 2008;102:1247.)
© 2008 American Heart Association, Inc.

Cellular Biology

Modulation of Endothelial Cell K_Ca3.1 Channels During Endothelium-Derived Hyperpolarizing Factor Signaling in Mesenteric Resistance Arteries

Kim A. Dora, Nicola T. Gallagher, Alister McNeish, Christopher J. Garland

From the Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, United Kingdom.

Correspondence to Christopher J. Garland, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, United Kingdom. E-mail c.j.garland{at}bath.ac.uk

Arterial hyperpolarization to acetylcholine (ACh) reflects coactivation of K_Ca3.1 (IK_Ca) channels and K_Ca2.3 (SK_Ca) channels in the endothelium that transfers through myoendothelial gap junctions and diffusible factor(s) to affect smooth muscle relaxation (endothelium-derived hyperpolarizing factor [EDHF] response). However, ACh can differentially activate K_Ca3.1 and K_Ca2.3 channels, and we investigated the mechanisms responsible in rat mesenteric arteries. K_Ca3.1 channel input to EDHF hyperpolarization was enhanced by reducing external [Ca²⁺]_o but blocked either with forskolin to activate protein kinase A or by limiting smooth muscle [Ca²⁺]_i increases stimulated by phenylephrine depolarization. Imaging [Ca²⁺]_i within the endothelial cell projections forming myoendothelial gap junctions revealed increases in cytoplasmic [Ca²⁺]_i during endothelial stimulation with ACh that were unaffected by simultaneous increases in muscle [Ca²⁺]_i evoked by phenylephrine. If gap junctions were uncoupled, K_Ca3.1 channels became the predominant input to EDHF hyperpolarization, and relaxation was inhibited with ouabain, implicating a crucial link through Na⁺/K⁺-ATPase. There was no evidence for an equivalent link through K_Ca2.3 channels nor between these channels and the putative EDHF pathway involving natriuretic peptide receptor-C. Reconstruction of confocal z-stack images from pressurized arteries revealed K_Ca2.3 immunostain at endothelial cell borders, including endothelial cell projections, whereas K_Ca3.1 channels and Na⁺/K⁺-ATPase ₂/₃ subunits were highly concentrated in endothelial cell projections and adjacent to myoendothelial gap junctions. Thus, extracellular [Ca²⁺]_o appears to modify K_Ca3.1 channel activity through a protein kinase A–dependent mechanism independent of changes in endothelial [Ca²⁺]_i. The resulting hyperpolarization links to arterial relaxation largely through Na⁺/K⁺-ATPase, possibly reflecting K⁺ acting as an EDHF. In contrast, K_Ca2.3 hyperpolarization appears mainly to affect relaxation through myoendothelial gap junctions. Overall, these data suggest that K⁺ and myoendothelial coupling evoke EDHF-mediated relaxation through distinct, definable pathways.

Key Words: potassium channel • endothelial cells • hyperpolarization • membrane potential • electrophysiology • vasodilation

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The EDHF Story: The Plot Thickens

Helena C. Parkington, Marianne Tare, and Harold A. Coleman
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