This Article Full Text Full Text (PDF) All Versions of this Article: 27/12/2496    most recent ATVBAHA.107.155341v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Larsen, B. T. Articles by Gutterman, D. D. Search for Related Content PubMed PubMed Citation Articles by Larsen, B. T. Articles by Gutterman, D. D. Related Collections Related Article

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2496.)
© 2007 American Heart Association, Inc.

Editorials

Epoxyeicosatrienoic Acids, TRP Channels, and Intracellular Ca²⁺ in the Vasculature

An Endothelium-Derived Endothelium-Hyperpolarizing Factor?

Brandon T. Larsen; David X. Zhang; David D. Gutterman

From the Departments of Pharmacology and Toxicology (B.T.L., D.D.G.), Medicine (D.X.Z., D.D.G.), and the Cardiovascular Center (B.T.L., D.X.Z., D.D.G.), Medical College of Wisconsin, and Veterans Administration Medical Center (D.D.G.), Milwaukee, Wisc.

Correspondence to David D. Gutterman, MD, Northwestern Mutual Professor of Medicine, Senior Associate Dean for Research, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail dgutt@mcw.edu

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Epoxyeicosatrienoic acids (EETs) are cytochrome P450-derived metabolites of arachidonic acid that function as endothelium-derived hyperpolarizing factors (EDHFs) in many species, including humans. Strictly speaking, an EDHF is a substance derived from endothelial cells that stimulates hyperpolarization of the underlying vascular smooth muscle cells (VSMCs) to elicit vasorelaxation. Although a physiological role of EETs in vasomotor¹ and nonvasomotor² regulation of the vasculature is now increasingly recognized, the underlying signaling mechanisms and cell types involved remain incompletely understood.

See page 2612

EETs are potent vasodilators that activate large-conductance Ca²⁺-activated potassium (BK_Ca) channels to induce membrane hyperpolarization.^3,4 In VSMCs, this hyperpolarization decreases Ca²⁺ influx through voltage-sensitive Ca²⁺ channels, ultimately leading to a global decrease in intracellular Ca²⁺ ([Ca²⁺]_i) with subsequent vasorelaxation (Figure). Electrophysiological studies indicate that EET-mediated activation of BK_Ca may involve an indirect membrane-delimited mechanism that involves ADP-ribosylation of G_s^4,5; however, specific EET receptors, if any, have not yet been isolated or cloned. Recent evidence suggests that nonselective cation "transient receptor potential" (TRP) channels may function as EET receptors per se, particularly the vanilloid type 4 (TRPV4) channel, which is directly activated by EETs.^6,7 Importantly, EET-induced Ca²⁺ influx through TRPV4 channels indirectly augments BK_Ca channel activity by stimulating localized ryanodine receptor-dependent Ca²⁺ release events (Ca²⁺ sparks) from the sarcoplasmic reticulum that then activate the BK_Ca channel⁷ without a concomitant increase in global cytosolic [Ca²⁺]_i (Figure).

View larger version (23K):   Figure. Proposed signaling pathways of EET-mediated vasodilation. On activation by bradykinin, endothelial cells release Ca2+ from intracellular . . . [Full Text of this Article]

Related Article:

Epoxyeicosatrienoic Acids Regulate Trp Channel–Dependent Ca²⁺ Signaling and Hyperpolarization in Endothelial Cells

Ingrid Fleming, Alexandra Rueben, Rüdiger Popp, Beate Fisslthaler, Susanne Schrodt, Anna Sander, Judith Haendeler, John R. Falck, Christophe Morisseau, Bruce D. Hammock, and Rudi Busse
Arterioscler Thromb Vasc Biol 2007 27: 2612-2618. [Abstract] [Full Text] [PDF]