Differential Effects of Cystathionine-γ-lyase–Dependent Vasodilatory H2S in Periadventitial Vasoregulation of Rat and Mouse Aortas

Abstract

BackgroundHydrogen sulfide (H2S) is a potent vasodilator. However, the complex mechanisms of vasoregulation by H2S are not fully understood. We tested the hypotheses that (1) H2S exerts vasodilatory effects by opening KCNQ-type voltage-dependent (Kv) K+ channels and (2) that H2S-producing cystathionine-γ-lyase (CSE) in perivascular adipose tissue plays a major role in this pathway.Methodology/Principal FindingsWire myography of rat and mouse aortas was used. NaHS and 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADTOH) were used as H2S donors. KCNQ-type Kv channels were blocked by XE991. 4-Propargylglycine (PPG) and ß-cyano-l-alanine (BCA), or 2-(aminooxy)-acetic acid (AOAA) were used as inhibitors of CSE or cystathionine-ß-synthase (CBS), respectively. NaHS and ADTOH produced strong vasorelaxation in rat and mouse aortas, which were abolished by KCNQ channel inhibition with XE991. Perivascular adipose tissue (PVAT) exerted an anticontractile effect in these arteries. CSE inhibition by PPG and BCA reduced this effect in aortas from rats but not from mice. CBS inhibition with AOAA did not inhibit the anticontractile effects of PVAT. XE991, however, almost completely suppressed the anticontractile effects of PVAT in both species. Exogenous l-cysteine, substrate for the endogenous production of H2S, induced vasorelaxation only at concentrations >5 mmol/l, an effect unchanged by CSE inhibition.Conclusions/SignficanceOur results demonstrate potent vasorelaxant effects of H2S donors in large arteries of both rats and mice, in which XE991-sensitive KCNQ-type channel opening play a pivotal role. CSE-H2S seems to modulate the effect of adipocyte-derived relaxing factor in rat but not in mouse aorta. The present study provides novel insight into the interaction of CSE-H2S and perivascular adipose tissue. Furthermore, with additional technical advances, a future clinical approach targeting vascular H2S/KCNQ pathways to influence states of vascular dysfunction may be possible.

Potassium-Channel-Independent Relaxing Influence of Adipose Tissue on Mouse Carotid Artery

“…There have been indications in the literature of differences in the vasodilator mechanism between rat and mouse adipose tissue [30]. Thus, while endogenous H 2 S has been suggested to be a direct mediator of the vasodilation in the rat, its effect seems less immediate in the mouse [30].…”

“…Thus, while endogenous H 2 S has been suggested to be a direct mediator of the vasodilation in the rat, its effect seems less immediate in the mouse [30]. However, rat and mouse adipose tissues were able to relax the rat carotid artery to a similar extent, suggesting the absence of major species differences in their function.…”

Regional differences in perivascular adipose tissue impacting vascular homeostasis

“…A possible role for a subfamiliy of K v channels (XE991-sensitive KCNQ) has been suggested [39,40], whereas ATP-dependent K + channels have only minor effects [41,42]. A similar but more paracrine ADRF/ K v mechanism may underlie the anticontractile effect of PVAT in murine mesenteric arteries [36,38] and aorta [43], as well as in rat mesenteric [36] and skeletal muscle arteries [40] (Figure 3). The involvement of calciumactivated potassium (K Ca ) channels has been excluded by both pharmacological tools and genetic ablation of these channels [36].…”

“…The nature of ADRF is unclear but may involve hydrogen sulfide in Sprague-Dawley rats [39,44], although not in mice [43]. PVAT-derived methyl palmitate may represent a putative ADRF, since it elicits rat aortic relaxation by activation of K v channels [45] (Figure 3).…”

Perivascular adipose tissue, inflammation and insulin resistance: link to vascular dysfunction and cardiovascular disease

“…In addition, it has been postulated that PVAT is able to induce vasodilatory and anti-contractile actions by secreting a PVAT-derived relaxing factor (termed PRVF). Although the nature of PVRF remains elusive, candidate molecules include adiponectin, nitric oxide (NO) [32], palmitate [33], hydrogen sulfide [34,35] and prostacyclin [34].…”