Title Edhf: an Update Rights This Work Is Licensed under a Creative Commons Attribution- Noncommercial-noderivatives 4.0 International License. Edhf: an Update

The endothelium controls vascular tone not only by releasing 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). However, this acronym includes different mechanisms. Arachidonic acid metabolites derived from the cyclooxygenases, lipoxygenases and cytochrome-P450 pathways, H2O2, CO, H2S and various peptides can be released by endothelial cells. These factors activate different families of K channels and hyperpolarization of the vascular smooth muscle cells contribute to the mechanisms leading to their relaxation. Additionally, another pathway associated with the hyperpolarization of both endothelial and vascular smooth muscle cells contributes also to endothelium-dependent relaxations (EDHF-mediated responses). These responses involve an increase in the intracellular Ca concentration of the endothelial cells followed by the opening of Ca-activated K channels of small and intermediate conductances (SKCa and IKCa). These channels show a distinct subcellular distribution, SKCa are widely distributed over the plasma membrane while IKCa are preferentially expressed in the endothelial projections toward the smooth muscle cells. Following SKCa activation, smooth muscle hyperpolarization is preferentially evoked by electrical coupling through myo-endothelial gap junctions, while following IKCa activation, potassium efflux can activate smooth muscle Kir2.1 and/or Na/K-ATPase. EDHF-mediated responses are altered by aging and various pathologies. Therapeutic interventions can restore these responses suggesting that the improvement of the EDHF pathway contributes to their beneficial effect. A better characterization of EDHF-mediated responses should allow determining whether or not new drugable targets can be identified for the treatment of cardiovascular diseases.