Endothelium-Derived Hyperpolarization and Coronary Vasodilation: Diverse and Integrated Roles of Epoxyeicosatrienoic Acids, Hydrogen Peroxide, and Gap Junctions

• Published in: Microcirculation (New York, N.Y. 1994) Vol. 23; no. 1; pp. 15 - 32
• Main Authors: Ellinsworth, David C., Sandow, Shaun L., Shukla, Nilima, Liu, Yanping, Jeremy, Jamie Y., Gutterman, David D.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.01.2016; Wiley Subscription Services, Inc
• Subjects: Acids; Animals; Ca2+-activated K+ channels; Calcium Signaling - physiology; connexins; coronary artery disease; coronary blood flow; Coronary Vessels - metabolism; cytochrome P450 epoxygenases; Eicosanoids - metabolism; Endothelium; Endothelium, Vascular - metabolism; endothelium-derived hyperpolarization; endothelium-derived hyperpolarizing factor; epoxyeicosatrienoic acids; gap junctions; Gap Junctions - metabolism; human coronary microcirculation; Humans; hydrogen peroxide; Hydrogen Peroxide - metabolism; mitochondrial electron transport chain; Muscle, Smooth, Vascular - metabolism; Myocardium - metabolism; myoendothelial signaling microdomains; NADPH oxidase; nitric oxide; transient receptor potential channels; Vasodilation - physiology; coronary artery disease; gap junctions; mitochondrial electron transport chain; nitric oxide; human coronary microcirculation; hydrogen peroxide; cytochrome P450 epoxygenases; transient receptor potential channels; connexins; myoendothelial signaling microdomains; endothelium-derived hyperpolarization; endothelium-derived hyperpolarizing factor; epoxyeicosatrienoic acids; NADPH oxidase; Ca2+-activated K+ channels; coronary blood flow
• ISSN: 1073-9688; 1549-8719
• DOI: 10.1111/micc.12255

Myocardial perfusion and coronary vascular resistance are regulated by signaling metabolites released from the local myocardium that act either directly on the VSMC or indirectly via stimulation of the endothelium. A prominent mechanism of vasodilation is EDH of the arteriolar smooth muscle, with EETs and H2O2 playing important roles in EDH in the coronary microcirculation. In some cases, EETs and H2O2 are released as transferable hyperpolarizing factors (EDHFs) that act directly on the VSMCs. By contrast, EETs and H2O2 can also promote endothelial KCa activity secondary to the amplification of extracellular Ca2+ influx and Ca2+ mobilization from intracellular stores, respectively. The resulting endothelial hyperpolarization may subsequently conduct to the media via myoendothelial gap junctions or potentially lead to the release of a chemically distinct factor(s). Furthermore, in human isolated coronary arterioles dilator signaling involving EETs and H2O2 may be integrated, being either complimentary or inhibitory depending on the stimulus. With an emphasis on the human coronary microcirculation, this review addresses the diverse and integrated mechanisms by which EETs and H2O2 regulate vessel tone and also examines the hypothesis that myoendothelial microdomain signaling facilitates EDH activity in the human heart.