Augmented H2S production via cystathionine-beta-synthase upregulation plays a role in pregnancy-associated uterine vasodilation†

Abstract

Endogenous hydrogen sulfide (H2S) synthesized via metabolizing L-cysteine by cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) is a potent vasodilator and angiogenic factor. The objectives of this study were to determine if human uterine artery (UA) H2S production increases with augmented expression and/or activity of CBS and/or CSE during the menstrual cycle and pregnancy and whether exogenous H2S dilates UA. Uterine arteries from nonpregnant (NP) premenopausal proliferative (pPRM) and secretory (sPRM) phases of the menstrual cycle and pregnant (P) women were studied. H2S production was measured by the methylene blue assay. CBS and CSE mRNAs were assessed by quantitative real-time PCR, and proteins were assessed by immunoblotting and semiquantitative immunofluorescence microscopy. Effects of H2S on rat UA relaxation were determined by wire myography ex vivo. H2S production was greater in NP pPRM and P than NP sPRM UAs and inhibited by the specific CBS but not CSE inhibitor. CBS but not CSE mRNA and protein were greater in NP pPRM and P than NP sPRM UAs. CBS protein was localized to endothelium and smooth muscle and its levels were in a quantitative order of P >NP UAs of pPRM>sPRM. CSE protein was localized in UA endothelium and smooth muscle with no difference among groups. A H2S donor relaxed P > NP UAs but not mesentery artery. Thus, human UA H2S production is augmented with endothelium and smooth muscle CBS upregulation, contributing to UA vasodilation in the estrogen-dominant physiological states in the proliferative phase of the menstrual cycle and pregnancy.

Estradiol‐17β stimulates H2S biosynthesis by ER‐dependent CBS and CSE transcription in uterine artery smooth muscle cells in vitro

“…E 2 β also stimulates CSE mRNA and protein expressions in UASMCs in vitro. This observation is unexpected because it not only contrasts to our in vivo findings that UASMC CSE mRNA and protein are not altered by estrogens in sheep (Lechuga et al, 2015) and women (Sheibani et al, 2017), but also other reports showing that E 2 β does not stimulate CSE expression in mouse mesenteric artery SMCs in vitro . Although the mechanisms underlying this discrepancy between the in vitro and in vivo findings is elusive, this raises a (Liao et al, 2005).…”

“…In cells expressing both ERα and ERβ, including UASMCs they can play similar or even opposite roles in mediating estrogen signaling (Zhang, Feng, Wang, Magness, & Chen, 2012 (Zhang et al, 2012). E 2 β stimulates both mRNA and protein expressions of CBS and CSE in vitro (current study) and CBS in vivo (Lechuga et al, 2015;Sheibani et al, 2017), suggesting that these stimulations occur at the level of transcription. Indeed, E 2 β stimulates > 4-fold increases in CBS and CSE promoter activity in UASMCs in vitro (Figure 4a).…”

“…| 9271 orchestrated vasodilator networks locally produced by UA endothelium, including NO (Rosenfeld et al, 2002;Valdes et al, 2009). Endothelial NO mediates <65% estrogen-induced uterine vasodilation Rosenfeld et al, 1996); however, the mechanisms in addition to endothelial NO have not been defined and whether UASMCs also produces vasodilators to mediate estrogeninduced uterine vasodilation is neglected. Our current findings, together with our recent in vivo work showing H 2 S as a novel UA vasodilator (Lechuga et al, 2015;Sheibani et al, 2017), provide a novel mechanism for estrogen-induced uterine vasodilation via SM-…”

E2β stimulates ovine uterine artery endothelial cell H2S production in vitro by estrogen receptor-dependent upregulation of cystathionine β-synthase and cystathionine γ-lyase expression†

“…In mammals, H 2 S potently dilates various vasculatures via activating ATP-dependent potassium (K ATP ) channel [21] and relaxes smooth muscle via activating large conductance calcium-activated potassium (BK Ca ) channel [22]. We recently reported that a slow-releasing H 2 S donor GYY4137 dose-dependently relaxes UAs from nonpregnant and pregnant rats, with significantly greater potency in the pregnant state and vascular bed specificity [23]. Others have shown H 2 S to be a placental vasodilator [24,25] and dysregulated CTH/H 2 S signaling in the placenta results in preeclampsia-like conditions [25].…”

GYY4137 Promotes Mice Feeding Behavior via Arcuate Nucleus Sulfur-Sulfhydrylation and AMPK Activation

“…Hydrogen sulfide (H 2 S) is produced endogenously in mammals by metabolism of sulfur-containing amino acids under the catalysis of special enzymes ( Predmore et al, 2012 ; Sheibani et al, 2017 ) and has been regarded as the third bio-active gas or gaseous signaling molecule by accumulated evidence ( Gadalla and Snyder, 2010 ; Predmore et al, 2012 ; Yu et al, 2017 ). H 2 S plays important physiological and pathological roles in many biological processes and acts as a critically functional regulator in several brain regions, such as the hippocampus and cerebral cortex ( Giuliani et al, 2013 ; Yakovlev et al, 2017 ; Zhu et al, 2017 ).…”