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Maternal regulation of embryonic growth: The role of vasoactive intestinal peptide

Department of Pediatrics, George Washington University, Washington, Washington, D.C., United States
Endocrinology (Impact Factor: 4.64). 03/1999; 140(2):917-24. DOI: 10.1210/en.140.2.917
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ABSTRACT Vasoactive intestinal peptide (VIP) is an important growth regulator of the embryonic day (E)9-E11 mouse. In comparably aged rat embryos, VIP messenger RNA (mRNA) is not detectable; however, peak concentrations of VIP in maternal rat serum indicate a nonembryonic source. In the current study, mouse maternal and embryonic tissues were examined from E6-E12. Although RT-PCR revealed VIP mRNA in E6-E7 conceptuses, by E8 (when extraembryonic tissues could be separated from the embryo), VIP mRNA was detected only in the decidua/trophoblast. Decidual/trophoblastic VIP mRNA decreased until E10, after which it was not detectable. VIP mRNA was not apparent in the embryo until E11-E12. At E9, VIP immunoreactivity was localized to abundant, diffuse cells in the decidua basalis, which were also immunoreactive for T cell markers. VIP binding sites were dense in the decidua/trophoblast at E6, but gradually decreased until E10, after which they were not apparent. VIP binding sites were detected in embryonic neuroepithelium by E9. The transient presence of VIP binding sites and mRNA in the decidua/trophoblast correlate with the critical period of VIP growth regulation, when VIP mRNA is absent in the embryo. These findings suggest that maternal lymphocytes are the source of VIP's regulating early postimplantation embryonic growth.

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    • "Endogenous actions of VIP were found in promoting hippocampal-dependent spatial discrimination in water maze learning (Glowa et al., 1992) and promoting embryonic brain development (Gressens et al., 1994; Spong et al., 1999; Zupan et al., 2000). The later does not relate directly to hippocampal function, is elicited by VIP originating in maternal placental lymphocytes (Gressens et al., 1994; Spong et al., 1999; Zupan et al., 2000) and is probably the cause for the cognitive impairment of the progeny of VIPdeficient female mice (Hill et al., 2007a; Stack et al., 2008). Thus, this study is of particular relevance to understand the role of endogenous VIP and hippocampal VPAC 1 receptors past the developmental stages, how they are endogenously activated and if they can constitute molecular targets to treat cognitive dysfunction. "
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    ABSTRACT: Vasoactive intestinal peptide (VIP), an important modulator of hippocampal synaptic transmission, influences exploration and hippocampal-dependent learning in rodents. Homosynaptic long-term depression (LTD) and depotentiation are two plasticity phenomena implicated in learning of behavior flexibility and spatial novelty detection. In this study, we investigated the influence of endogenous VIP on LTD and depotentiation induced by low-frequency stimulation (1 Hz, 900 pulses) of the hippocampal CA1 area in vitro in juvenile and young adult rats, respectively. LTD and depotentiation were enhanced by the VIP receptor antagonist Ac-Tyr(1) , D-Phe(2) GRF (1-29) and the selective VPAC1 receptor antagonist, PG 97-269, but not the selective VPAC2 receptor antagonist, PG 99-465. This action was mimicked by an anti-VIP antibody, suggesting that VIP, and not pituitary adenylate cyclase-activating polypeptide (PACAP), is the endogenous mediator of these effects. Selective inhibition of PAC1 receptors with PACAP (6-38) enhanced depotentiation, but not LTD. VPAC1 receptor blockade also revealed LTD in young adult rats, an effect abolished by the GABAA antagonist bicuculline, evidencing an involvement of GABAergic transmission. We conclude that inhibition of LTD and depotentiation by endogenous VIP occurs through VPAC1 receptor-mediated mechanisms and suggests that disinhibition of pyramidal cell dendrites is the most likely physiological mechanism underlying this effect. As such, VPAC1 receptor ligands may be considered promising pharmacological targets for treatment of cognitive dysfunction in diseases involving altered GABAergic circuits and pathological saturation of LTP/LTD like Down's syndrome and temporal lobe epilepsy. © 2014 Wiley Periodicals, Inc.
    Hippocampus 11/2014; 24(11). DOI:10.1002/hipo.22316 · 4.30 Impact Factor
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    • "Tregs, helping to maintain immunotolerance in different animal models including nonobese diabetic (NOD) mice (Rosignoli et al. 2006, Gonzalez Rey & Delgado 2007). Finally, VIP participates in the maternal regulation of embryonic growth in rodents during the early post-implantation period and the blockade of VIP function induced growth retardation and microcephaly (Gressens et al. 1994, Spong et al. 1999, Rangon et al. 2006). "
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    ABSTRACT: Among several factors known to modulate embryo implantation and survival, uterine quiescence and neovascularization, maternal immunotolerance through the Th1/Th2 cytokine balance towards a Th2 profile, local regulatory T-cell (Treg) activation, and high levels of progesterone were assigned a prominent role. Vasoactive intestinal peptide (VIP) is a neuroimmunopeptide that has anti-inflammatory effects, promotes Th2 cytokines and CD4(+)CD25(+)FOXP3(+) Treg activation, and stimulates exocrine secretion, smooth muscle relaxation, and vasodilatation favoring uterus quiescence. The goal of the present work was to explore the participation of VIP in the implantation sites of normal and pregnant prediabetic nonobese diabetic (NOD) females, a mouse strain that spontaneously develops an autoimmune exocrinopathy similar to Sjögren's syndrome. Our results indicate a reduction in litter size from the third parturition onwards in the NOD female lifespan with increased resorption rates. Progesterone systemic levels were significantly decreased in pregnant NOD mice compared with BALB/c mice, although the allogeneic response to progesterone by spleen cells was not impaired. VIP receptors, Vipr1 and Vipr2 (Vpac1 and Vpac2), were expressed at the implantation sites and VIP induced leukemia inhibitory factor (LIF) and Treg marker expression in both strains; however, a reduced Vip expression was found in NOD implantation sites. We conclude that the reduced birth rate at 16-week-old NOD mice with a Th1 systemic cytokine profile involves resorption processes with a lower expression of VIP at the sites of implantation, which acts as a local inducer of pro-implantatory LIF and Treg activation.
    Reproduction 08/2009; 138(4):733-42. DOI:10.1530/REP-09-0171
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    • "Prior to E12 in the mouse, when the embryonic yolk sac circulation is in intimate contact with the maternal decidua of the pregnant uterus, both VIP and its mRNA are abundant in the decidua, where immunoreactive VIP has been localized to gamma delta T lymphocytes (Spong et al., 1999). The mRNA for VIP in the uterine decidua was most abundant from E7–E10, peaked at E8, and was no longer detectable by E11–E12 (Spong et al., 1999). VIP has been shown to cross the developing placenta during early embryogenesis (Hill et al., 1996), and the maternal uterine tissues are the likely source of the peptide acting on embryonic VIP receptors to regulate growth and development in the mouse embryo. "
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    ABSTRACT: Pharmacological studies indicate that vasoactive intestinal peptide (VIP) may be necessary for normal embryonic development in the mouse. For example, VIP antagonist treatment before embryonic day 11 resulted in developmental delays, growth restriction, modified adult brain chemistry and reduced social behavior. Here, developmental milestones, growth, and social behaviors of neonates of VIP-deficient mothers (VIP +/-) mated to VIP +/- males were compared with the offspring of wild type mothers (VIP +/+) mated to VIP +/+ and +/- males, to assess the contributions of both maternal and offspring VIP genotype. Regardless of their own genotype, all offsprings of VIP-deficient mothers exhibited developmental delays. No delays were seen in the offspring of wild type mothers, regardless of their own genotype. Body weights were significantly reduced in offspring of VIP-deficient mothers, with VIP null (-/-) the most affected. Regardless of genotype, all offspring of VIP-deficient mothers expressed reduced maternal affiliation compared with wild type offspring of wild type mothers; +/- offspring of wild type mothers did not differ in maternal affiliation from their wild type littermates. Play behavior was significantly reduced in all offsprings of VIP-deficient mothers. Maternal behavior did not differ between wild type and VIP-deficient mothers, and cross-fostering of litters did not change offspring development, indicating that offspring deficits were induced prenatally. This study illustrated that the VIP status of a pregnant mouse had a greater influence on the growth, development and behavior of her offspring than the VIP genotype of the offspring themselves. Deficiencies were apparent in +/+, +/- and -/- offspring born to VIP-deficient mothers; no deficiencies were apparent in +/- offspring born to normal mothers. These results underscore the significant contribution of the uterine environment to normal development and indicate a potential usefulness of the VIP knockout mouse in furthering the understanding of neurodevelopmental disorders with social behavior deficits such as autism.
    International Journal of Developmental Neuroscience 09/2008; 26(5):423-34. DOI:10.1016/j.ijdevneu.2008.03.002 · 2.92 Impact Factor
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