Expression of cystathionine β-synthase and cystathionine γ-lyase in human pregnant myometrium and their roles in the control of uterine contractility

Abstract

Background: Human uterus undergoes distinct molecular and functional changes during pregnancy and parturition. Hydrogen sulfide (H 2S) has recently been shown to play a key role in the control of smooth muscle tension. The role of endogenous H 2S produced locally in the control of uterine contractility during labour is unknown. Methodology/Principal Findings: Human myometrium biopsies were obtained from pregnant women undergoing cesarean section at term. Immunohistochemistry analysis showed that cystathionine-γ-lyase (CSE) and cystathionine-β-synthetase (CBS), the principle enzymes responsible for H 2S generation, were mainly localized to smooth muscle cells of human pregnant myometrium. The mRNA and protein expression of CBS as well as H 2S production rate were down-regulated in labouring tissues compared to nonlabouring tissues. Cumulative administration of L-cysteine (10 -7-10 -2 mol/L), a precursor of H 2S, caused a dose-dependent decrease in the amplitude of spontaneous contractions in nonlabouring and labouring myometrium strips. L-cysteine at high concentration (10 -3 mol/L) increased the frequency of spontaneous contractions and induced tonic contraction. These effects of L-cysteine were blocked by the inhibitors of CBS and CSE. Pre-treatment of myometrium strips with glibenclamide, an inhibitor of ATP-sensitive potassium (K ATP) channels, abolished the inhibitory effect of L-cysteine on spontaneous contraction amplitude. The effects of L-cysteine on the amplitude of spontaneous contractions and baseline muscle tone were less potent in labouring tissues than that in nonlabouring strips. Conclusion/Significance: H 2S generated by CSE and CBS locally exerts dual effects on the contractility of pregnant myometrium. Expression of H 2S synthetic enzymes is down-regulated during labour, suggesting that H 2S is one of the factors involved in the transition of pregnant uterus from quiescence to contractile state after onset of parturition. © 2011 You et al.