Epoxyeicosatrienoic Acids, TRP Channels, and Intracellular Ca 2+ in the Vasculature

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 (BKCa) 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 BKCa may involve an indirect membrane-delimited mechanism that involves ADP-ribosylation of Gsα4,5; 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 BKCa channel activity by stimulating localized ryanodine receptor-dependent Ca2+ release events (Ca2+ sparks) from the sarcoplasmic reticulum that then activate the BKCa channel7 without a concomitant increase in global cytosolic [Ca2+]i (Figure). Figure. Proposed signaling pathways of EET-mediated vasodilation. On activation by bradykinin, endothelial cells release Ca2+ from intracellular stores to promote formation of the vasodilator compounds NO or EETs. As outlined in the present study by Fleming et al,16 EETs act in an autocrine …