Select Nutrients in the Ovine Uterine Lumen. VIII. Arginine Stimulates Proliferation of Ovine Trophectoderm Cells Through MTOR-RPS6K-RPS6 Signaling Cascade and Synthesis of Nitric Oxide and Polyamines1

Kim, Jin‐Young; Burghardt, Robert C.; Wu, Guoyao; Johnson, Greg A.; Spencer, Thomas E.; Bazer, Fuller W.

doi:10.1095/biolreprod.110.085753

Cited by 78 publications

(63 citation statements)

References 77 publications

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“…Amino acids are critical to pregnancy because of its influence on embryo and fetal growth and development (Kim et al 2011, Wu 2010. Our previous study demonstrated that dietary arginine supplementation during early pregnancy enhanced the number of embryos implanted and the expression of iNOS and eNOS in implantation sites was increased in rats fed the arginine-supplemented diet (Zeng et al 2008).…”

Section: Discussionmentioning

confidence: 98%

“…Intrauterine injection of DFMO on d4 of pregnancy inhibited embryonic development and embryogenesis in rats (Méndeza et al 1983). Previous study demonstrated that arginine stimulated proliferation of ovine trophectoderm cells via mTOR signaling pathway and nitric oxide and polyamines (Kim et al 2011). We hypothesize that dietary arginine supplementation during early pregnancy may activate PI3K-PKB-mTOR signaling pathway, which could increase the expression of uterine iNOS and eNOS and inhibition of polyamine synthesis could increase NO production and release.…”

Section: Introductionmentioning

confidence: 85%

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Arginine enhances embryo implantation in rats through PI3K/PKB/mTOR/NO signaling pathway during early pregnancy

Zeng¹,

Mao²,

Huang³

et al. 2013

Reproduction

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Our previous study has demonstrated that dietary arginine supplementation during early pregnancy enhanced embryo implantation in rats. However, the mechanism was not clear. The objective of this study was to determine the mechanism that arginine enhanced embryo implantation during early pregnancy. Rats were fed the basal diets supplemented with 1.3% (wt:wt) L-arginine-HCl or 2.2% (wt:wt) L-alanine (isonitrogenous control) once pregnancy. On d4 of pregnancy, rats were given intrauterine injection of L-NG-nitro arginine methyl ester (L-NAME, nitric oxide synthase inhibitor), a-difluoromethylornithine (DFMO, polyamine synthesis inhibitor), wortmannin (PI3K inhibitor), or rapamycin (mTOR inhibitor). On d7 of pregnancy, rats were killed. Intrauterine injection of L-NAME decreased the implantation sites, while dietary arginine supplementation increased the implantation sites. Intrauterine injection of DFMO decreased the pregnancy rate, which was reversed by dietary arginine supplementation. Intrauterine injection of rapamycin or wortmannin inhibited embryo implantation. However, dietary arginine supplementation did not reverse this inhibition. Western blot analysis revealed that the expression of uterine p-PKB and p-S6K1 was greater in rats fed the arginine-supplemented diet in the presence of L-NAME treatment compared with rats fed the control diet. In the presence of DFMO treatment, the expression of uterine iNOS and eNOS was significantly enhanced in the arginine group compared with the control group. Similarly, intrauterine injection of wortmannin or rapamycin decreased the expression of uterine iNOS and eNOS, which was enhanced by dietary arginine supplementation. These data indicated that dietary arginine supplementation during early pregnancy could enhance embryo implantation through stimulation of PI3K/PKB/mTOR/NO signaling pathway.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 85%

Arginine enhances embryo implantation in rats through PI3K/PKB/mTOR/NO signaling pathway during early pregnancy

Zeng¹,

Mao²,

Huang³

et al. 2013

Reproduction

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“…Cells grown in serum-free specialized medium and specialized medium containing 10% FBS served as negative and positive controls, respectively. Cell numbers were determined as described previously (44)(45)(46)(47)(48).…”

Section: Methodsmentioning

confidence: 99%

“…The effects of glucose and fructose on phosphorylation of RPS6K, EIF4EBP1, and RPS6 were determined by immunofluorescence microscopy as previously described (44,45). Cells probed with rabbit anti-human polyclonal p-RPS6K IgG (Thr421/Ser424) at a 1:200 di- Fig.…”

Section: Methodsmentioning

confidence: 99%

Functional roles of fructose

Kim

Song

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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During the periimplantation period of pregnancy, pig blastocysts undergo morphological changes and differentiation requiring secretion and transport of nutrients (histotroph) into the uterine lumen. Of these nutrients, glucose is converted to fructose, an isomer of glucose, by conceptus trophectoderm. Although glucose is an energy source for proliferation and growth of mammalian cells, the role of fructose in uterine histotroph is unclear although it is the most abundant hexose sugar in fetal blood and fluids of ungulate mammals (e.g., cows, sheep, and pigs). In this study, we used porcine trophectoderm cells to determine that fructose increased cell proliferation, as did glucose. Western blot analyses of porcine trophectoderm cell extracts revealed that fructose increased the abundance of phosphorylated-RPS6K, -EIF4EBP1, and -RPS6 over basal levels within 30 min, and those levels remained elevated to 120 min. Phosphorylation of both RPS6K and EIF4EBP1 proteins in response to fructose was inhibited by inhibitors of both PI3K and MTOR. Further, when we investigated the inhibition of glutamine-fructose-6-phosphate transaminase 1 (GFPT1) by azaserine (an inhibitor of GFPT1) and GFPT1 siRNA, we found that MTOR-RPS6K and MTOR-EIF4EBP1 signaling in response to fructose is mediated via GFPT1 activation and the hexosamine pathway. We further demonstrated that fructose stimulates the production of hyaluronic acid via GFPT1 and the hexosamine biosynthesis pathway. Collectively, these results demonstrate critical roles for fructose that are mediated via the hexosamine biosynthesis pathway to stimulate MTOR cell signaling, proliferation of porcine trophectoderm cells, and synthesis of hyaluronic acid, a significant glycosaminoglycan in the pregnant uterus.trophoblast | glycosaminoglycans D omestic livestock species are invaluable animal models used extensively in research relevant to human and veterinary reproductive medicine as well as basic biological and biomedical sciences (1, 2). In particular, the ewe is an established animal model for studies of intrauterine growth restriction during fetal life that is a predisposition for the adult onset of metabolic disease (3). Ewes have a protracted periimplantation period of pregnancy, a relatively short period of gestation, and are well suited for metabolic studies to assess temporal and cell-specific changes in gene expression in response to various hormones, growth factors, and nutrients that are relevant to human and veterinary medicine and basic aspects of reproductive biology. Although fructose clearly is the major hexose sugar in fetal blood and fetal fluids of ungulate species such as sheep and pigs, it is largely ignored with respect to function because it is not metabolized via the glycolytic pathway or the Krebs cycle as an energy source. Here we provide evidence that fructose affects multiple metabolic pathways critical to pregnancy and metabolism in multiple organ systems.Fructose is the most abundant hexose sugar in fetal fluids of ungulate mammals (4-6). Fructose ...

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“…Therefore, signaling pathways mediated by Arg to effect proliferation of ovine trophectoderm (oTr) cells were assessed using NO donors (SNAP and DETA) and putrescine (a precursor for spermidine and spermine; Kim et al, 2011). L-NAME (an inhibitor of NOS) and Nor-NOHA (an inhibitor of arginase) were also used to assess pathways activated via Arg.…”

Section: Argininementioning

confidence: 99%

Pregnancy recognition signals in mammals: the roles of interferons and estrogens

Bazer

Johnson

2017

Anim Reprod

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Reproduction is a highly complex biological process requiring a dialogue between the developing conceptus (embryo-fetus and associated placental membranes) and maternal uterus which must be established during the peri-implantation period for pregnancy recognition signaling and regulation of gene expression by uterine epithelial and stromal cells. The uterus provide a microenvironment in which molecules secreted by uterine epithelia or transported into the uterine lumen represent histotroph or the secretome required for growth and development of the conceptus and receptivity of the uterus to implantation by the conceptus. Pregnancy recognition signaling as related to sustaining the functional lifespan of the corpora lutea (CL) which produce progesterone; the hormone of pregnancy essential for uterine functions that support implantation and placentation required for successful outcomes of pregnancy. It is within the periimplantation period that most embryonic deaths occur in mammals due to deficiencies attributed to uterine functions or failure of the conceptus to develop appropriately, signal pregnancy recognition and/or undergo implantation and placentation. The endocrine status of the pregnant female and her nutritional status are critical for successful establishment and maintenance of pregnancy. The challenge is to understand the complexity of key mechanisms that are characteristic of successful reproduction and to use that knowledge to enhance fertility and reproductive health of animals including nonhuman primates. It is important to translate knowledge gained from studies of animals to address issues of fertility and reproductive health in humans.

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Select Nutrients in the Ovine Uterine Lumen. VIII. Arginine Stimulates Proliferation of Ovine Trophectoderm Cells Through MTOR-RPS6K-RPS6 Signaling Cascade and Synthesis of Nitric Oxide and Polyamines1

Cited by 78 publications

References 77 publications

Arginine enhances embryo implantation in rats through PI3K/PKB/mTOR/NO signaling pathway during early pregnancy

Arginine enhances embryo implantation in rats through PI3K/PKB/mTOR/NO signaling pathway during early pregnancy

Functional roles of fructose

Pregnancy recognition signals in mammals: the roles of interferons and estrogens

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