Published online before print March 16, 2006, doi: 10.1161/01.ATV.0000217611.81085.c5
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© 2006 American Heart Association, Inc.
Brief Reviews |
Endothelium-Derived Hyperpolarizing Factor
Where Are We Now?
From the Department of Angiology (M.F.), Institut de Recherches Servier, Suresnes, France; and the Department of Pharmacology (P.M.V.), Faculty of Medicine, University of Hong Kong.
Correspondence to Paul M. Vanhoutte, Department of Pharmacology, 2/F, Laboratory Block, Faculty of Medicine Building, 21, Sassoon Road, Pokfulam, University of Hong Kong, Hong Kong, China. E-mail vanhoutte.hku{at}hku.hk
Series Editor: Frank M. Faraci Previous Brief Reviews in this Series:
•Wolfrum S. Jensen KS, Liao JK. Endothelium-dependent efects of statins. 2003;23:729–736.
•Frank PG, Woodman SE, Park DS, Lisanti MP. Caveolin, caveolae, and endothelial cell function. 2003;23:1161–1168.
•Katusic ZS, Caplice NM, Nath KA. Nitric oxide synthase gene transfer as a tool to study biology of endotheial cells. 2003;23:1990–1995.
•Faraci FM, Didion SP. Vascular protection: superoxide dismutase isoforms in the vessel wall. 2004;24:1367–1373.
The endothelium controls vascular tone not only by releasing nitric oxide (NO) and prostacyclin but also by other pathways causing hyperpolarization of the underlying smooth muscle cells. This characteristic was at the origin of the denomination endothelium-derived hyperpolarizing factor (EDHF). We know now that this acronym includes different mechanisms. In general, EDHF-mediated responses involve an increase in the intracellular calcium concentration, the opening of calcium-activated potassium channels of small and intermediate conductance and the hyperpolarization of the endothelial cells. This results in an endothelium-dependent hyperpolarization of the smooth muscle cells, which can be evoked by direct electrical coupling through myo-endothelial junctions and/or the accumulation of potassium ions in the intercellular space. Potassium ions hyperpolarize the smooth muscle cells by activating inward rectifying potassium channels and/or Na+/K+-ATPase. In some blood vessels, including large and small coronary arteries, the endothelium releases arachidonic acid metabolites derived from cytochrome P450 monooxygenases. The epoxyeicosatrienoic acids (EET) generated are not only intracellular messengers but also can diffuse and hyperpolarize the smooth muscle cells by activating large conductance calcium-activated potassium channels. Additionally, the endothelium can produce other factors such as lipoxygenases derivatives or hydrogen peroxide (H2O2). These different mechanisms are not necessarily exclusive and can occur simultaneously.
EDHF-mediated responses involve the activation of endothelial potassium channels. The hyperpolarization of the smooth muscle is evoked through myo-endothelial junctions and/or the accumulation of K+ in the intercellular space. Additionally, the endothelium releases factors that can hyperpolarize the smooth muscle cells such as reactive oxygen species and arachidonic acid metabolites.
Key Words: CNP • cytochrome P450 • cyclooxygenase • EDHF • gap junction • lipoxygenaseNO • potassium channels • prostacyclin
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