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ABSTRACT: The effect of sodium nitroprusside (SNP), a donor of nitric oxide, on meiotic maturation of mouse oocytes was studied by injecting
Nw-nitro-L-arginine methyl ester (L-NAME) intra-peritoneal (ip), a nitric oxide synthase inhibitor, or culturing oocytes in
the medium supplemented with L-NAME or hypoxanthine (HX) to arrest the spontaneous oocyte maturationin vitro. The results showed that the inhibitory effect of L-NAME by injecting 10 mg/kg ip on extrusion of the first polar body only
could be reversed by injecting 2.5 mg/kg SNP with L-NAME simultaneously (P < 0.05). Half an hour later ten mice died when given 10 mg/kg SNP ip. The treatment of some concentrations of SNP (10−7, 10−6, 10−5 mol/L) significantly stimulated meiotic maturation to metaphase II stages in cumulus enclosed oocytes in the presence of
HX. However, other concentrations of SNP (10−8, 10−4, 10−3 mol/L) had no effect on HX-arrested oocyte meiotic maturation. The optimal concentration of SNP on CEOs had no effect on
DOs. The dose of 10−3 mol/LL-NAME demonstrated a significant suppression in formation of PB1, but not in GVBD. This inhibition was reversed by the addition of SNP. These results indicated that the physiological levels
of NO produced by cumulus cells could stimulate meiotic maturation of mouse oocytes bothin vivo andin vitro.
Keywordssodium nitroprusside-oocyte maturation-first polar body-germinal vesicle breakdown-mouse
Chinese Science Bulletin 04/2012; 48(1):72-75. · 1.32 Impact Factor
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ABSTRACT: Reduced litter sizes in mice missing pentraxin 3 (Ptx3) have been attributed to fertilization failure. However, our global gene expression studies showed high uterine Ptx3 expression at the implantation site in mice, suggesting its role in blastocyst implantation. We initiated molecular and genetic studies in mice to explore the importance of uterine Ptx3 in this process. We found that Ptx3 is expressed in a unique and transient fashion at implantation sites. With the initiation of implantation on midnight of Day 4 of pregnancy, Ptx3 is expressed exclusively in stromal cells at the site of blastocysts. On Day 5, its expression is more intense in decidualizing stromal cells, but it disappears on Day 6. The expression again becomes evident in the deciduum on Day 7, followed by a more robust expression on Day 8, particularly at the antimesometrial pole. From Day 9, with the initiation of placentation, Ptx3 expression becomes undetectable. These results suggest a role for PTX3 in implantation and decidualization. Indeed, deletion of Ptx3 results in both compromised implantation and decidualization. Interleukin 1B (IL1B), a known inducer of Ptx3, is also transiently expressed in stromal cells at the implantation site, suggesting that IL1B is an inducer of uterine Ptx3 expression. In fact, uterine Ptx3 expression follows that of Il1b induced by lipopolysaccharide treatment on Day 7 of pregnancy. Collectively, these findings provide evidence for an important role for PTX3 in implantation and decidualization. This study has clinical implications, since PTX3 is expressed in the receptive endometrium, and trophoblast cells influence decidual Ptx3 expression in humans.
Biology of Reproduction 10/2007; 77(3):425-32. · 4.01 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptor (PPAR) delta is a member of the nuclear hormone receptor superfamily. PPARdelta may ameliorate metabolic diseases such as obesity and diabetes. However, PPARdelta's role in colorectal carcinogenesis remains controversial. Here, we present genetic and pharmacologic evidence demonstrating that deletion of PPARdelta decreases intestinal adenoma growth in Apc(Min/+) mice and inhibits tumor-promoting effects of a PPARdelta agonist GW501516. More importantly, we found that activation of PPARdelta up-regulated VEGF in colon carcinoma cells. VEGF directly promotes colon tumor epithelial cell survival through activation of PI3K-Akt signaling. These results not only highlight concerns about the use of PPARdelta agonists for treatment of metabolic disorders in patients who are at high risk for colorectal cancer, but also support the rationale for developing PPARdelta antagonists for prevention and/or treatment of cancer.
Proceedings of the National Academy of Sciences 01/2007; 103(50):19069-74. · 9.68 Impact Factor
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ABSTRACT: Synchronized preimplantation embryo development and passage through the oviduct into the uterus are prerequisites for implantation, dysregulation of which often leads to pregnancy failure in women. Cannabinoid/endocannabinoid signaling via cannabinoid receptor CB1 is known to influence early pregnancy. Here we provide evidence that a critical balance between anandamide synthesis by N-acylphosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and its degradation by fatty acid amide hydrolase (FAAH) in mouse embryos and oviducts creates locally an appropriate "anandamide tone" for normal development of embryos and their oviductal transport. FAAH inactivation yielding higher anandamide or experimentally induced higher cannabinoid [(-)-Delta9-tetrahydrocannabinol] levels constrain preimplantation embryo development with aberrant expression of Cdx2, Nanog, and Oct3/4, genes known to direct lineage specification. Defective oviductal embryo transport arising from aberrant endocannabinoid signaling also led to deferred on-time implantation and poor pregnancy outcome. Intercrossing between wild-type and Faah-/- mice rescued developmental defects, not oviductal transport, implying that embryonic and maternal FAAH plays differential roles in these processes. The results suggest that FAAH is a key metabolic gatekeeper, regulating on-site anandamide tone to direct preimplantation events that determine the fate of pregnancy. This study uncovers what we believe to be a novel regulation of preimplantation processes, which could be clinically relevant for fertility regulation in women.
Journal of Clinical Investigation 09/2006; 116(8):2122-31. · 15.39 Impact Factor
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ABSTRACT: Implantation requires reciprocal interaction between blastocysts and a receptive uterus. In mice, one important player in this dialogue involves endocannabinoid signaling via cannabinoid receptor CB1. Anandamide is an endogenous cannabinoid ligand, and its levels are spatiotemporally regulated in the uterus during early pregnancy, showing lower levels in the receptive uterus and at the implantation site. However, the mechanism by which differential uterine anandamide gradients are established under different pregnancy status is not clearly understood. Using multiple approaches, we show here that uterine anandamide levels conducive to implantation are primarily regulated by spatiotemporal expression of Nape-Pld, the gene encoding N-acylphosphatidylethanolamine-hydrolyzing phospholipase D that generates anandamide. The expression is well correlated with its activity and anandamide levels. This study is clinically relevant, since elevated anandamide levels in peripheral circulation are associated with spontaneous pregnancy failure in women.
Journal of Biological Chemistry 07/2005; 280(25):23429-32. · 4.77 Impact Factor
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ABSTRACT: Ectopic pregnancy is a major reproductive health issue. Although other underlying causes remain largely unknown, one cause of ectopic pregnancy is embryo retention in the fallopian tube. Here we show that genetic or pharmacologic silencing of cannabinoid receptor CB1 causes retention of a large number of embryos in the mouse oviduct, eventually leading to pregnancy failure. This is reversed by isoproterenol, a beta-adrenergic receptor agonist. Impaired oviductal embryo transport is also observed in wild-type mice treated with methanandamide. Collectively, the results suggest that aberrant cannabinoid signaling impedes coordinated oviductal smooth muscle contraction and relaxation crucial to normal oviductal embryo transport. Colocalization of CB1 and beta2-adrenergic receptors in the oviduct muscularis implies that a basal endocannabinoid tone in collaboration with adrenergic receptors coordinates oviductal motility for normal journey of embryos into the uterus. Besides uncovering a new regulatory mechanism, this study could be clinically relevant to ectopic pregnancy.
Nature Medicine 11/2004; 10(10):1074-80. · 22.46 Impact Factor
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ABSTRACT: Successful implantation absolutely depends on the reciprocal interaction between the implantation-competent blastocyst and the receptive uterus. Expression and gene targeting studies have shown that leukemia inhibitory factor (LIF), a cytokine of the IL-6 family, and Hoxa-10, an abdominalB-like homeobox gene, are crucial to implantation and decidualization in mice. Using these mutant mice, we sought to determine the importance of Msx-1 (another homeobox gene formerly known as Hox-7.1) and of Wnt4 (a ligand of the Wnt family) signaling in implantation because of their reported functions during development. We observed that Msx-1, Wnt4, and a Wnt antagonist sFRP4 are differentially expressed in the mouse uterus during the periimplantation period, suggesting their role in implantation. In addition, we observed an aberrant uterine expression of Msx-1 and sFRP4 in Lif mutant mice, and of Wnt4 and sFRP4 in Hoxa-10 mutant mice, further reinforcing the importance of these signaling pathways in implantation. Collectively, the present results provide evidence for a novel cytokine-homeotic-Wnt signaling network in implantation.
Molecular Endocrinology 06/2004; 18(5):1238-50. · 4.54 Impact Factor
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ABSTRACT: Mammalian fertility absolutely depends on synchronized development of the blastocyst to the stage when it is competent to implant, and the uterus to the stage when it is receptive to implantation. However, the molecular basis for the reciprocal interaction between the embryo and the uterus remains largely unexplored. One potentially important mechanism involves signaling between an evolutionarily conserved G protein-coupled protein cannabinoid receptor, CB1, that is expressed at high levels on the surface of the trophectoderm and anandamide (N-arachi-donoylethanolamine), an endocannabinoid ligand found to be produced at higher levels by the uterus before implantation and then down-regulated at the time of implantation. Using genetic, pharmacological, and physiological approaches, we show here that anandamide within a very narrow range regulates blastocyst function and implantation by differentially modulating mitogen-activated protein kinase signaling and Ca2+ channel activity via CB1 receptors. Anandamide at a low concentration (7 nM) induces extracellular regulated kinase phosphorylation and nuclear translocation in trophectoderm cells without influencing Ca2+ channels, and renders the blastocyst competent for implantation in the receptive uterus. In contrast, anandamide at a higher concentration (28 nM) inhibits Ca2+ channel activity and blastocyst competency for implantation without influencing mitogen-activated protein kinase signaling. Besides uncovering a potentially important regulatory mechanism for synchronizing blastocyst and uterine competency to implantation, this observation has high clinical relevance, because elevated levels of anandamide induce spontaneous pregnancy loss in women.
Proceedings of the National Academy of Sciences 01/2004; 100(25):14914-9. · 9.68 Impact Factor
