No abstract

No abstract

Embryo retention in the fallopian tube is thought to lead to ectopic pregnancy, which is a significant cause of morbidity. Hydrogen sulphide (H 2 S) is a gaseotransmitter produced mainly by cystathionine-g-lyase and cystathionine-b-synthase. Here we show that cystathionine-g-lyase and cystathionine -b-synthase are ubiquitously distributed in human fallopian tube epithelium and that H 2 S signalling relaxes the spontaneous contraction of the human oviduct. Furthermore, an aberration in H 2 S signalling, either silenced or enhanced activity induced by pharmacologic or genetic methods, causes embryo retention and developmental delay in the mouse oviduct, which is partly reversed by administration of either GYY4137, a slow-releasing H 2 S donor, or NaHS. Our findings reveal a new regulatory mechanism for oviductal embryo transport.

Context Dysregulated immune hemostasis occurs in unexplained recurrent spontaneous abortion (URSA). Synthesized by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), hydrogen sulfide (H2S) promotes regulatory T-cell differentiation and regulates immune hemostasis; yet, its role in URSA is elusive. Objective To determine if H2S plays a role in early pregnancy and if dysregulated H2S signaling results in RSA. Design First-trimester placenta villi and decidua were collected from normal and URSA pregnancies. Protein expression were examined by immunohistochemistry and immunoblotting. Human trophoblast HTR8/SVneo and JEG3 cells were treated with H2S donors; HTR8/SVneo cells were transfected with CBS RNAi or cDNA. Cell migration and invasion were determined by trans-well assays; trophoblast transcriptomes were determined by RNA-seq. Wild-type, CBS-deficient, and CBA/J × DBA/2 mice were treated with CBS and CSE inhibitors or H2S donors to determine the role of H2S in early pregnancy in vivo. Results CBS and CSE proteins showed cell-specific expressions but only CBS decreased in the villous cytotrophoblast in URSA vs. normal subjects. H2S donors promoted migration and invasion and MMP-2 and VEGF expression in HTR8/SVneo and JEG3 cells, similar to forced CBS expression in HTR8/SVneo cells. The CBS-responsive transcriptomes in HTR8/SVneo cells contained differentially regulated genes, i.e., IL-1R and PGTS2, that are associated with nuclear factor-κB-mediated inflammatory response. In vivo, dysregulated CBS/H2S signaling significantly increased embryonic resorption and decidual Th1/Th2 imbalance in mice, which was partially rescued by H2S donors. Conclusion CBS/H2S signaling maintains early pregnancy possibly via regulating maternal-fetal interface immune hemostasis, offering opportunities for H2S-based immunotherapies for URSA.

Acid-sensing ion channels (ASICs) belong to the family of the epithelial sodium channel/degenerin (ENaC/DEG) and are activated by extracellular protons. They are widely distributed within both the central and peripheral nervous systems. ASICs were modified by the activation of γ-aminobutyric acid receptors (GABAA), a ligand-gated chloride channels, in hippocampal neurons. In contrast, the activity of GABAA receptors were also modulated by extracellular pH. However so far, the mechanisms underlying this intermodulation remain obscure. We hypothesized that these two receptors-GABAA receptors and ASICs channels might form a novel protein complex and functionally interact with each other. In the study reported here, we found that ASICs were modified by the activation of GABAA receptors either in HEK293 cells following transient co-transfection of GABAA and ASIC1a or in primary cultured dorsal root ganglia (DRG) neurons. Conversely, activation of ASIC1a also modifies the GABAA receptor-channel kinetics. Immunoassays showed that both GABAA and ASIC1a proteins were co-immunoprecipitated mutually either in HEK293 cells co-transfected with GABAA and ASIC1a or in primary cultured DRG neurons. Our results indicate that putative GABAA and ASIC1a channels functionally interact with each other, possibly via an inter-molecular association by forming a novel protein complex.