Endothelial control of vasodilation: integration of myoendothelial microdomain signalling and modulation by epoxyeicosatrienoic acids

Endothelium-derived epoxyeicosatrienoic acids (EETs) are fatty acid epoxides that play an important role in the control of vascular tone in selected coronary, renal, carotid, cerebral and skeletal muscle arteries. Vasodilation due to endothelium-dependent smooth muscle hyperpolari- zation (EDH) has been suggested to involve EETs as a transferable endothelium-derived hyperpolarizing factor. However, this activity may also be due to EETs interacting with the components of other primary EDH-mediated vaso- dilator mechanisms. Indeed, the transfer of hyperpolarization initiated in the endothelium to the adjacent smooth muscle via gap junction connexins occurs separately or synergisti- cally with the release of K + ions at discrete myoendothelial microdomain signalling sites. The net effects of such activity are smooth muscle hyperpolarization, closure of voltage- dependent Ca 2+ channels, phospholipase C deactivation and vasodilation. The spatially localized and key compo- nents of the microdomain signalling complex are the inositol 1,4,5-trisphosphate receptor-mediated endoplasmic reticu- lum Ca 2+ store, Ca 2+ -activated K + (KCa), transient receptor potential (TRP) and inward-rectifying K + channels, gap junctions and the smooth muscle Na + /K + -ATPase. Of these, TRP channels and connexins are key endothelial effector targets modulated by EETs. In an integrated manner, endog- enous EETs enhance extracellular Ca 2+ influx (thereby amplifying and prolonging KCa-mediated endothelial hyper- polarization) and also facilitate the conduction of this hyper- polarization to spatially remote vessel regions. The contri- bution of EETs and the receptor and channel subtypes in- volved in EDH-related microdomain signalling, as a candi- date for a universal EDH-mediated vasodilator mechanism, vary with vascular bed, species, development and disease and thus represent potentially selective targets for modulat- ing specific artery function.