The endothelium at the brink of calamity in storage disease: more than just overloaded with junk?

Abstract

This editorial refers to ‘Globotriaosylceramide leads to KCa3.1 channel dysfunction: a new insight into endothelial dysfunction in Fabry disease’ by S. Park et al ., pp. 290–299, this issue. The endothelium crucially controls the contractile status of vascular smooth muscle and thereby vascular diameter. This is achieved by the release of dilating endothelial autacoids such as nitric oxide (NO), prostaglandins, and a third factor that elicits relaxation through smooth muscle hyperpolarization and is therefore known as ‘endothelium-derived hyperpolarizing factor’ (EDHF). Although the importance of EDHF is well accepted, its chemical nature is still elusive, and a wide range of agents, such as K+ ions, eicosanoids, H2O2, H2S, or C-type natriuretic peptide, have been suggested to serve as EDHF. Despite this diversity, it is firmly established that endothelial hyperpolarization is critical to initiate EDHF-type dilation. It is either achieved by releasing one of the above-mentioned molecules or by a direct current transfer from endothelium to smooth muscle via the gap junctions that interconnect these cells.1 The initial endothelial hyperpolarization results from opening of Ca2+-activated K+-channels (KCa), which have been identified as KCa3.1 and/or KCa2.3 (also named IKCa and SKCa, respectively) by pharmacological blockers as well as by genetic approaches. Both endothelial KCa channels are activated by Ca2+ and are voltage independent, which is an important biophysical feature that prevents their inactivation by the ensuing hyperpolarization, thus …