EDHF Redux: EETs, TRPV4, and Ca 2+ Sparks

Abstract

See related article, pages 1270–1279 Over the past two decades the complexity of the molecular processes underlying endothelial-dependent vascular relaxation has gradually become apparent. After the ground breaking discovery of the role of NO as a major endothelium-derived relaxant factor (EDRF), evidence emerged indicating the existence of a hyperpolarizing factor (endothelium-derived hyperpolarizing factor [EDHF]) with actions distinct from the cyclase-dependent relaxations associated with endothelial production of NO and prostacyclin.1–3 The specific molecules and vascular relaxation mechanisms underlying this intensely studied phenomenon have been difficult to establish, however. H2O2, K ions, and epoxygenase products have all been implicated as the EDHF, and evidence has suggested in turn that the mechanism by which EDHF relaxes arteries involves diffusion of the substance to smooth muscle and direct gating effects on calcium-activated K+ (maxiK) channels,4,5 actions mediated through endothelial small and intermediate conductance Ca2+-activated K+ (SK and IK) channels,6–8 and passive ionic effects associated with an extracellular accumulation of K+ ions.9 To further muddy these dark waters, recent evidence has implicated TRPV4 channels in EDHF signaling in several vascular preparations. In this issue of Circulation Research , Earley and colleagues10 identify a new putative mechanism and one that links EDHF to the regulation of Ca2+ release by ryanodine receptors (RYR), thereby forging a mechanistic link between EDHF and the well described local gating of large conductance Ca2+-activated K+ …