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    • br Signals transmitted via MEGJ MEGJ facilitate the direct t

    2021-11-25


    Signals transmitted via MEGJ MEGJ facilitate the direct transfer of ion currents or small molecules between EC and VSMC. Molecules passing through MEGJ are mainly second messengers such as Ca2+, IP3, and cAMP [31,32,] or endothelium-derived hyperpolarization (EDH) signals [34, 35, 36]. Moreover, MEGJ serve as a feedback mechanism to limit vasoconstriction (see Figure 2). Wei et al. have recently demonstrated that sympathetic nerve-evoked constriction elevates endothelial Ca2+ signals and activates intermediate conductance Ca2+-activated K+ (IKCa) channels to oppose vasoconstriction. The IP3 flux through MEGJ after α1-adrenoceptor stimulation attenuates vasoconstriction via hyperpolarization []. Isakson et al. have shown that IP3 signals generated in VSMC following stimulation can be transferred to EC, but not vice versa [31]. Because of localized expression of the IP3-receptor1 at the endothelial endoplasmic reticulum at MEGJ, myoendothelial transferred IP3 leads to elevated levels of endothelial Ca2+ where it induces NO production and/or EDH and, lastly, attenuates VSMC constriction by acting as a negative feedback mechanism. In contrast, IP3 diffusing from EC to VSMC is quickly degraded in VSMC, hence attenuating its vasoconstrictor effect in these cells [31] (Figure 2). Further, in the same vessel types but in different tissues there are apparently different degrees of MEGJ coupling. In mouse cremaster NS 11021 australia weak myoendothelial coupling has been demonstrated [38]. However, in hamster cheek pouch arterioles dye transfer is detectable, but exclusively from EC to VSMC [39], suggesting a tissue type-related control of Cx in MEGJ.
    Regulation of MEGJ MEGJ communication is probably differentially regulated in EC or VSMC via Cx interacting proteins or molecules affecting signalling enzymes controlling post-translational modifications or Cx expression []. Endothelial Cx expression appears to be highly dependent on flow conditions in vivo. For example, depending on local shear stress, Cx37 and Cx43 are differentially expressed within the endothelium of different aortic sections [40]. The quantity of MEGJ is dependent additionally on the vessel type and increases generally with decreasing vessel diameter [26,41]. However, the number of MEGJ [42] and the shape of myoendothelial microprojections [43] determine the extent to which myoendothelial communication is established. A high degree of MEGJ coupling is established, for example, to enable the negative feedback mechanism between VSMC and EC mainly after VSMC stimulation [29] or to enhance EDH conduction [44], while low coupling is necessary to allow the forwarding and preservation of action potentials in lymphangions []. Furthermore, in lower saphenous arteries inhibition of MEGJ increases the interendothelial distributed Ca2+ signal and prevents signal transfer to VSMC [17]. In renal arteries inhibition of MEGJ significantly reduces the EDH response; however, it is partly rescued by increased potassium efflux from VSMC [46].
    MEGJ in vascular dysfunction Vascular dysfunction during atherosclerosis is associated with substantial changes of endothelial Cx expression and function. Expression of Cx37 and Cx40 disappears in the endothelium covering atherosclerotic plaques, whereas expression of endothelial Cx43 is induced [63,64]. Similar expression patterns are found after application of oxidation products of lipoprotein-derived phospholipids and correlate with an increased Cx43 phosphorylation at Tyr265, probably mediated by Src [65], which is associated with reduced coupling between EC and VSMC [53]. Additionally, it is likely that the abundance of inflammatory mediators in atherosclerosis may be involved in the modification of Cx expression and MEGJ. Indeed lipopolysaccharides, tumor necrosis factor-α, and interleukin-1β, selectively inhibit human MEGJ in vitro without affecting GJ between the respective homologous cell populations [66]. Further, in response to low shear stress an altered endothelial Cx40/Cx43 expression and reduced myoendothelial coupling has been found to be involved in the endothelium mediated VSMC phenotype switch (occurring during atherosclerosis) [67]. Moreover, in the ApoE−/− mouse model of atherogenesis, VSMC express less total Cx43 but elevated levels of phosphorylated Cx43 at Ser279/282 and Ser368, induced by two different oxidized phospholipid species [68]. Both Cx43 phosphorylation through MAPK (Ser279/282) and PKC (Ser368) have been previously shown to reduce GJ communication [69,70]. Interestingly, phosphorylation at Ser279/282 but not at Ser368 correlates with increased proliferation rates of VSMC, as induced by oxidized phospholipid derivatives [68].