Ghrelin misbalance affects mice embryo implantation and pregnancy success by uterine immune dysregulation and nitrosative stress

LUQUE, EUGENIA MERCEDES; DÍAZ-LUJÁN, CINTIA MARÍA; PAIRA, DANIELA ANDREA; DE LOREDO, NICOLÁS; TORRES, PEDRO JAVIER; CANTARELLI, VERÓNICA INÉS; FRETES, RICARDO; MOTRICH, RUBÉN DARÍO; MARTINI, ANA CAROLINA

Frontiers in Endocrinology

Lausanne: Frontiers Media S.A.

Año: 2023 vol. 14

Introduction: In a previous study we found that ghrelin (Ghrl) misbalance duringthe peri-implantation period significantly impaired fetus development. In thisstudy we aimed to evaluate the putative mechanisms underlying these effects,including embryo implantation success, uterine nitric oxide synthase (NOS)activity, nitric oxide synthesis and the inflammatory/immune uterine profile.Methods: Ghrelin misbalance was induced by injecting 4nmol/animal/day ofGhrl (hyperghrelinemia) or 6nmol/animal/day of a Ghrl antagonist (Ant: (D-Lys3)GHRP-6) from day 3 to 8 of pregnancy. Control animals (C) were injected with devehicle. Females were euthanized at pregnancy day 8 and their uteri excised inorder to evaluate: the percentage of reabsorbed embryos (microscopically),eNOS, iNOS and nytrotirosine expression (by immunohistochemistry), nitritesynthesis (by Griess technique), VEGF, IL-10, IL-17, IL-6, MMP9 and GM-CSFexpression (by qPCR) and leukocyte infiltration by flow cytometry (evaluating Tcells, NK cells, granulocytes, dendritic cells and macrophages).Results: Ant-treatment significantly increased the percentage of reabsorbedembryos and the uterine expression of eNOS, iNOS and nytrotirosine. (D-Lys3)GHRP-6-treatment increased also the expression of the inflammatory cytokinesIL-6, IL-17 and MMP9, and decreased that of IL-10 (anti-inflammatory).Moreover, Ant-treatment increased also the NK cells population and that ofCD11b+ dendritic cells; and decreased T cells percentages. Similarly,hyperghrelinemia showed a significant increase vs. C on eNOS, iNOS andnytrotirosineuterine expression and a decrease in T cells percentages.Conclusion: Ghrl misbalance during the peri-implantation period induces proinflammatorychanges and nitrosative stress in the gravid uterus, impairingsignificantly embryo implantation and/or development.