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

Abstract

Myocardial perfusion and coronary vascular resistance are regulated by signalling metabolites released from the local myocardium that act either directly on the vascular smooth muscle cells (VSMC) or indirectly via stimulation of the endothelium. A prominent mechanism of vasodilation is endothelium-derived hyperpolarization (EDH) of the arteriolar smooth muscle, with epoxyeicosatrienoic acids (EETs) and hydrogen peroxide (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 Ca2+-activated K+ channel 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 signalling 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 signalling facilitates EDH activity in the human heart.

Regulation of Coronary Blood Flow

“…Arachidonic acid is found in the plasma membrane of nearly every cell in the body. Once released by the actions of phospholipases, there are three potential fates for free arachidonic acid in the vasculature: (i) functionally washed out of the system; (ii) reincorporated into the plasma membrane; and (iii)metabolized into different substrates down one of three major metabolic pathways involving either the cyclooxygenase, lipoxygenase or cytochrome P-450 pathway (289,307). In particular, specific metabolites of the cyclooxygenase pathway termed prostaglandins, which won Bergstrom, Samuelsson and Vane the Nobel Prize in 1982 (80,82,83,357,735), include a variety of vasoactive compounds, such as the vasodilator prostaglandin I 2 (PGI 2 or prostacyclin) as well as the vasoconstrictor compounds prostaglandin H 2 , prostaglandin F2α and thromboxane A 2 (which are discussed in Section Cyclooxygenase Derived Constricting Factors ).…”

“…Identification of another broad family of endothelial-derived vasodilators came about from observations of sustained endothelial-dependent hyperpolarization and vasodilation in the presence of combined blockade of nitric oxide and cyclooxygenase (307, 340, 347, 419, 421, 719). Following their initial characterization in the early 1990’s, numerous endothelial-derived hyperpolarizing factors (EDHFs) have been identified.…”

“…Following their initial characterization in the early 1990’s, numerous endothelial-derived hyperpolarizing factors (EDHFs) have been identified. Although the list of potential versus accepted EDHFs continues to evolve, several factors that have been recognized include cytochrome P-450 metabolites of arachidonic acid [epoxyeicosatrienoic acids (EETs)], H 2 O 2 , potassium, H 2 S, anandamide, and nitroxyl (63, 65, 296, 307, 371, 619, 646, 784). Of these factors, there is growing consensus, largely based on the work of the Gutterman laboratory [see (289,307,419,528) for review], that endothelial-derived H 2 O 2 and fatty acid epoxides EETs are important regulators of coronary vascular tone in response to a variety of stimuli, including cyclic stretch, shear stress (flow-induced dilation), and physiological agonists such as bradykinin and acetylcholine (143, 306, 859) (Fig.…”

“…21). These EDHFs mediate vasodilation via direct effects on vascular smooth muscle and may facilitate amplification and/or prolongation of endothelial cell hyperpolarization through the opening of K Ca channels (307). The importance of K Ca channels to endothelial-dependent hyperpolarization is highlighted by the studies which have demonstrated that inhibition of small (SK Ca ), intermediate (IK Ca ), and/or large-conductance (BK Ca ) K Ca channels abolishes hyperpolarization of coronary arteries from humans (64, 112, 604, 679, 680, 831), pigs (63, 134, 140, 297, 970), rats (24, 927), guinea pigs (190, 191, 1001), dogs (594, 743), and mice (640, 750).…”

Communication Is Key: Mechanisms of Intercellular Signaling in Vasodilation

“…Being the innermost layer of the vessel wall, the endothelium can quickly sense and respond to changes in circulating humoral factors as well as physical effects of blood flow itself, resulting in signal transmission to the underlying smooth muscle cells to adjust vascular tone. (4) While the list of endothelial-derived diffusible vasoactive agents continues to expand, the paradigm is shifting from one where autocoids released from the endothelium act on vascular smooth muscle cells, to a more globally coordinated model involving electrotonic and mechanical communication along and through the vascular wall. Control of vascular tone operates in a larger arena with multiple inputs from adjacent vascular segments.…”