Endothelium‐dependent hyperpolarizations in health and disease

An official satellite symposium of the Annual Meeting of the Scandinavian Physiological Society was held in Nyborg, Denmark, from 14 to 17 September 2015 to focus on the latest developments in knowledge on endothelium-dependent responses and their impact on vascular biology in general and on their dysfunction contributing to cardiovascular diseases. Researcher from all over the world joined this event and discussed signalling mechanisms in resistance vessels with emphasis on the importance of endothelium-dependent hyperpolarizations. The meeting resulted in 11 publications in this issue Acta Physiologica which describe large findings in small blood vessels. Indeed, the Scandinavian Physiological Society had judged the topic of the symposium to be worth of selection as an Acta Physiologica International Symposium. The intention of these symposia is to favour interactions between Nordic scientists and colleagues working in similar fields in other countries. Furthermore, the symposium in Nyborg was the continuation of a long-standing series (starting in 1995) of meetings, initiated by Paul M. Vanhoutte and Michel F el etou and previously held at the Abbaye des Vaux de Cernay (France) and focusing on endothelium-dependent hyperpolarizations and the released factors/signals underlying these as they affect vascular function. Endothelium-dependent hyperpolarizations, which again were the focus of the symposium in Nyborg, play a particularly important role in endotheliumdependent vasodilatations in resistance arteries. Calcium influx stimulated by receptor activation or shear stress leads to the opening of Ca-activated K channels of small and intermediate conductance and subsequent hyperpolarization of the endothelial cells. This leads to hyperpolarization of the underlying vascular smooth muscle cells and vasodilatation. Previous meetings were named EDHF, standing for endothelium-derived factor. However, at the last meeting in Vaux de Cernay, the consensus was to omit F from the abbreviation and hence from the title of subsequent meetings (Feletou & Vanhoutte 2013), as we now know that endothelial cell hyperpolarization can, at least in some blood vessels, be conducted to vascular smooth muscle via gap junctions. However, many factors are released by the endothelium and play a role in the endothelium-dependent hyperpolarizations/ relaxations. These factors were also discussed at the meeting giving a brilliant overview of the latest findings within this field. This issue also covers widely topics from endothelial microdomains/myoendothelial coupling, to EDH heterogeneity and the role of other regulators of vascular function, contributed by leaders in the field. For example, EDH and the signalling pathways involved are reviewed by Garland & Dora (2016) in ‘EDH: Endothelium-dependent hyperpolarization and microvascular signaling’. The authors emphasize the involvement of the small and intermediate Ca-activated K channels which are localized in microdomains containing myoendothelial connections enabling the hyperpolarization to spread to the underlying vascular smooth muscle cells. An important feature of the vasculature is the ability to conduct dilatations along the vessel wall to ensure adequate blood supply in response to increased metabolic demands. Both ATP and K can evoke these dilatations, and they can therefore play an important role for regulation of blood flow. Kim Dora describes this phenomenon in her personal contribution entitled ‘Conducted dilatation to ATP and K in rat skeletal muscle arterioles’ (Dora 2016). The role of Ca-activated K channels is further emphasized by Ulf Simonsen and colleagues in ‘Emerging roles of calcium-activated K channels and TRPV4 channels in lung oedema and pulmonary circulatory collapse’. The authors focus on the TRPV4 channels which activate the Ca-sensitive K channels as opening of TRPV4 channels leads to calcium influx. The interplay between these channels plays an important role for pulmonary arterial dilatation, and the intermediate-conductance Ca-sensitive K channels may be a potential therapeutic target to prevent pulmonary circulatory collapse. An important source of calcium in the endothelial cells is the endoplasmic reticulum (ER). The control of this vital source of activator ion depends on microdomains within the cell allowing separate ER involvement through tubules which project to restricted areas and allows for spatial and temporal signalling. This phenomenon, with its large impact on cellular physiology and organism homoeostasis, is reviewed by Brant Isakson in ‘ER mediated signaling in cellular microdomains’ (Biwer & Isakson 2016). The importance of hyperpolarization-mediated factors such as epoxyeicosatrienoic acids (EETs) is well known in the field. The group of William B. Campbell investigated the vascular effects of the 12/15-lipoxygenase arachidonic acid metabolites, trioxilin A3 and C3 and hepoxilin A3 which are