Gasotransmitters in pregnancy: from conception to uterine involution

Abstract

Gasotransmitters are endogenous small gaseous messengers exemplified by nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S or sulfide). Gasotransmitters are implicated in myriad physiologic functions including many aspects of reproduction. Our objective was to comprehensively review basic mechanisms and functions of gasotransmitters during pregnancy from conception to uterine involution and highlight future research opportunities. We searched PubMed and Web of Science databases using combinations of keywords nitric oxide, carbon monoxide, sulfide, placenta, uterus, labor, and pregnancy. We included English language publications on human and animal studies from any date through August 2018 and retained basic and translational articles with relevant original findings. All gasotransmitters activate cGMP signaling. NO and sulfide also covalently modify target protein cysteines. Protein kinases and ion channels transduce gasotransmitter signals, and co-expressed gasotransmitters can be synergistic or antagonistic depending on cell type. Gasotransmitters influence tubal transit, placentation, cervical remodeling, and myometrial contractility. NO, CO, and sulfide dilate resistance vessels, suppress inflammation, and relax myometrium to promote uterine quiescence and normal placentation. Cervical remodeling and rupture of fetal membranes coincide with enhanced oxidation and altered gasotransmitter metabolism. Mechanisms mediating cellular and organismal changes in pregnancy due to gasotransmitters are largely unknown. Altered gasotransmitter signaling has been reported for preeclampsia, intrauterine growth restriction, premature rupture of membranes, and preterm labor. However, in most cases specific molecular changes are not yet characterized. Nonclassical signaling pathways and the crosstalk among gasotransmitters are emerging investigation topics.

Keywords: 3-mercaptosulfurtransferase (3-MST); ATP-gated potassium channel (KATP); calcium-gated potassium channel (BKCa); carbon monoxide (CO); cystathionine-β-synthase (CBS); cystathionine-γ-lyase (CSE); decidua; extravillous trophoblast (EVT); gasotransmitter; heme oxygenase (HO); hydrogen sulfide (H2S); maternal–fetal interface; myometrium; nitric oxide (NO); nitric oxide synthase (NOS); paraventricular nucleus (PVN); parturition; placenta; pregnancy; uterus.

Figure 1.

Nitric oxide metabolism and regulation. (A) Intermediates, enzymes (bold, italics), and biochemical effects (shaded boxes) of classical, S-nitrosothiol, and cytotoxic NO signaling. Gray text and arrows indicate excretion pathways. Arg: arginine. Cit: citrulline. GR: GSH reductase. SM: smooth muscle. (B–D) Transcriptional and post-translational regulation of neuronal (B), inducible (C), and endothelial (D) nitric oxide synthase (NOS) isoforms. Kinases, phosphoregulatory sites, and inhibitory ubiquitin ligases are shown. Green +’s and red X’s indicate positive and negative regulation, respectively.

Figure 2.

Carbon monoxide metabolism and regulation. (A) Intermediates, enzymes (bold, italics), and biochemical effects (shaded boxes) of classical and cGMP-independent CO signaling. RBCs: red blood cells, (B) Transcriptional and post-translational regulation of HO-1 and HO-2.

Figure 3.

Sulfide metabolism and regulation. (A) Intermediates, enzymes (bold, italics), and biochemical effects (shaded boxes) of classical and persulfide-based sulfide signaling. B/I/SK_Ca: Ca²⁺-gated large, intermediate, and small conductance K⁺ channels. GSSH: GSH persulfide. Protein-SSH: Proteins with persulfidated cysteine residues. ROS: reactive oxygen species. (B–D) Transcriptional and post-translational regulation of CBS (B), CSE (C), and 3-MST (D).

Figure 4.

Integration of gasotransmitter metabolism. Sulfide synthesis via reverse transsulfuration generates NH₄⁺ and αKB, which can produce NO and CO via the urea cycle and heme metabolism, respectively. αKB: α-ketobutyrate. CP: carbamoyl phosphate. Ctn: Cystathionine. Orn: ornithine. Ser: Serine. Double arrowheads indicate pathways in which multiple intermediates have been omitted for clarity

Figure 5.

Gasotransmitters regulate fallopian tube transit, decidualization, implantation, and placentation. (A) Fallopian tube transit. ET1 from the fallopian endothelium upregulates iNOS in the fallopian ampulla. Deficiencies in CBS hinder transit of fertilized embryos. Depending on its concentration, NO stimulates or inhibits pregnancy-sustaining progesterone (P₄) by the corpus luteum (CL). (B) Decidualization and implantation. HO-1 drives proliferation of ectoplacental cone (EPC) cells. Decidual eNOS, nNOS, iNOS, and SOD1 increase in abundance as the endometrium decidualizes, and NOS activity facilitates implantation. ICM: inner cell mass, GC: Giant cells. (C) Developmental changes at the maternal-fetal interface (MFI). During pregnancy, CO facilitates remodeling of maternal spiral arteries (red circle) into low-resistance, high-flow canals (red patch) surrounding the placental villi (yellow, green, and black branched structure). Endothelial NOS potentiates placental amino acid transport from maternal circulation (red) to fetal circulation (black). On the fetal side, eNOS, both HO isoforms, CBS, and CSE facilitate dilation and angiogenesis of fetal vasculature (black). AAs: amino acids. SA: spiral arteries. Green circles and yellow layers represent cytotrophoblasts and the syncytiotrophoblast, respectively. (D) EVT motility. Wnt and PI3K pathways both activate iNOS, which inhibits EVT apoptosis and promotes cell motility. HO-1 and PPARγ inhibit EVT motility. Green +’s and red X’s denote up- and downregulation, respectively.

Figure 6.

Gasotransmitters regulate maternal vascular tone and immunotolerance. (A) Prior to pregnancy, nNOS in the paraventricular nucleus of the hypothalamus (H) limits sympathetic activity in the rostral ventrolateral medulla (M) and inhibits endothelin 1 (ET1)-mediated release of vasopressin from the pituitary (P), both of which reduce peripheral vascular resistance. During pregnancy, rising E₂ inhibits PVN nNOS and stimulates PVN eNOS expression via ERβ. ERα facilitates E₂-mediated eNOS activation in the periphery by promoting S1177 and curtailing T495 phosphorylation. AVP: Vasopressin. (B) CO promotes recruitment of uNKs to the decidua, which enhance fetal alloimmune tolerance via endometrial IL-15 and CBS. Inducible NOS and HO-1 activity attenuate T_CTX maturation, while persulfidation of NFYB enhances naïve T^DN differentiation into T_regs. Endo: endometrium. T^DN: double-negative (CD4⁻ CD8⁻) naïve T cells.

Figure 7.

Gasotransmitters in parturition. (A) Regulation of myometrial contractility (depicted cell is a uterine myocyte). NOS activity in myocytes or adjacent endothelium inhibits contraction by stimulating BK_Ca and raising GSNO levels. GSNO is tocolytic. Myocyte CBS curtails GPR109A activity, which reduces OTR signaling. CBS and/or CSE also activate K_ATP and potentiate an unidentified protein downstream of Cl_Ca that induces tocolysis. Sulfide and GSNO produce ONSS⁻, which promotes uterine contractility. F_2αR: receptor for prostaglandin F_2α PLC: phospholipase C. (B) Cervical remodeling. In early pregnancy, P₄ inhibits iNOS synthesis. More iNOS and less SOD1 near parturition allows ONOO⁻ to accumulate, which stimulates prostaglandin F_2α synthesis. Prostaglandin F_2α in turn promotes PR-A accumulation and thus blocks P₄ perception. (C) Rupture of fetal membranes. Inducible NOS activity drives formation of ONOO⁻, which accelerates membrane rupture. By an unknown mechanism, CBS activity promotes PGDH-dependent prostaglandin F_2α degradation, which slows fetal membrane rupture.

Figure 8.

Summary schematic of gasotransmitter-mediated processes in pregnancy. Blue dotted, red dashed, and yellow solid lines denote NO, CO, and sulfide, respectively.