Modulation of vascular tone has been subject to intense investigations for more than three decades. Numerous studies have looked into signalling pathways where interaction between endothelial cells (ECs) and smooth muscle cells (SMCs) regulates the vascular circulation. This signalling induces SMC contraction/relaxation which is dependent on cytosolic calcium ([Ca2+]i) concentrations and investigations on how this [Ca2+]i level is regulated has opened up myriad upstream signalling routes. Probably most importantly, the discovery of the endothelium-derived relaxing factor (EDRF) in 1980 (Furchgott & Zawadzki, 1980) and its identification as the gasotransmitter nitric oxide (NO) in 1987 (Palmer et al. 1987) broadened our understanding of regulation of vascular tone. Since then, other freely diffusible endogenous gasotransmitters have been identified, namely carbon monoxide (CO) and hydrogen sulfide (H2S). However, NO and CO (although less efficient than NO) can exert their effects though activation of soluble guanylyl cyclase and subsequent production of cGMP, whereas H2S does not. All of these gasotransmitters exhibit strong cytotoxic properties when reaching higher levels and are also involved in non-vascular signalling pathways, i.e. in nervous or immune systems, and are important signalling molecules in certain disease conditions (Steinert et al. 2010; Skovgaard et al. 2011). Work published by Liang et al. (2012) in a recent issue of The Journal of Physiology describes more evidence for the vascular actions of H2S. The study elegantly shows how H2S modulates Ca2+ signalling in pig cerebral arteriolar SMCs by increasing Ca2+ spark frequency, which ultimately decreases global [Ca2+]i concentrations. The authors suggest that H2S enhances levels of ryanodine receptor (RyR)-sensitive Ca2+ stores and increases the frequency of calcium sparks and transient Ca2+-activated K+ channel (BK) currents leading to SMC hyperpolarization and subsequent vessel relaxation. Single channel analyses revealed that the increased frequencies of transient BK currents are not matched by changes in single channel current amplitudes but are solely due to greater open probability. SR Ca2+ content depends on the fine balance between SR uptake and release (Bassani et al. 1995) and it would be interesting to continue this study to determine whether H2S can regulate Ca2+ uptake mechanisms, such as sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) activities or other store release pathways, such as inositol 1,4,5-trisphosphate (IP3) receptor signalling. As RyR-mediated Ca2+ release provides the main pathway for Ca2+ sparks, the questions now arises which of the reported Ca2+ release routes are affected by H2S, including single RyR within release clusters without activation of the remaining channels, isolated un-clustered RyRs or non-RyR leak pathways. H2S is produced in various tissues, including the nervous and cardiovascular systems, from l-cysteine, catalysed by cystathionine-β-synthase (CBS) and/or cystathionine-γ-lyase (CSE). More recently, additional pathways have been identified cysteine aminotransferase (CAT) and 3-mercaptopyrovate sulfuresterase (3MST) with CSE being expressed in the SMCs and ECs but CAT/3MST only localized in the endothelium (Fig. 1). Depending on its concentration, H2S induces variable vasoactive effects in different vascular beds. The liver has high H2S-generating capacity and may be responsible for maintaining the concentration of H2S in the blood, which has been reported to be in the range of 1–160 μmol l−1 although the detection methods do not always give consistent results. Figure 1 Schematic diagram of gasotransmitter signalling in the vasculature Similarly to NO, exogenous application of H2S donors leads to a peak release of H2S followed by rapid metabolism and drop of vasoactive concentrations thereby altering its potential to induce relaxation over time. The complexity and concentration dependency of H2S signalling becomes apparent when comparing vasorelaxing and vasoconstricting effects (reviewed by Skovgaard et al. 2011). In light of these difficulties, an approach where endogenously produced H2S is investigated might help to explain observed inconsistent vascular responses to different H2S concentrations. H2S donor application relaxes rat aortic rings or human mammary arteries via opening of ATP-sensitive K+ (KATP) channels (Zhao et al. 2001) and direct actions of H2S on KATP channels have been reported. In addition H2S modulates voltage-gated K+ (KCNQ) and BK currents in various preparations; however, the exact mechanisms by which H2S acts on BK have to be elucidated. Discrepancies in modulatory effects on BK are most likely due to different concentrations used or tissue variability, which accounts for differences in BK α- and β-subunit expression. The current paper by Liang et al. (2012) provides new insights into the mechanisms by which BK channels are regulated in response to H2S signalling, namely via enhancing Ca2+ spark frequency. Nevertheless, the ultimate response of SMCs is the reduction of voltage-gated Ca2+ channel open probability in order to achieve vascular relaxation and the study by Liang et al. (2012) greatly enhances our understanding of vascular signalling pathways downstream of H2S.
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Jun 28, 2023
Lixin Zhang + 7
Open Access
