RESUMO
Although neutrophils are known to be fundamental in controlling innate immune responses, their role in regulating adaptive immunity is just starting to be appreciated. We report that human neutrophils exposed to pregnancy hormones progesterone and estriol promote the establishment of maternal tolerance through the induction of a population of CD4+ T cells displaying a GARP+CD127loFOXP3+ phenotype following antigen activation. Neutrophil-induced T (niT) cells produce IL-10, IL-17, and VEGF and promote vessel growth in vitro. Neutrophil depletion during murine pregnancy leads to abnormal development of the fetal-maternal unit and reduced empbryo development, with placental architecture displaying poor trophoblast invasion and spiral artery development in the maternal decidua, accompanied by significantly attenuated niT cell numbers in draining lymph nodes. Using CD45 congenic cells, we show that induction of niT cells and their regulatory function occurs via transfer of apoptotic neutrophil-derived proteins, including forkhead box protein 1 (FOXO1), to T cells. Unlike in women with healthy pregnancies, neutrophils from blood and placental samples of preeclamptic women fail to induce niT cells as a direct consequence of their inability to transfer FOXO1 to T cells. Finally, neutrophil-selective FOXO1 knockdown leads to defective placentation and compromised embryo development, similar to that resulting from neutrophil depletion. These data define a nonredundant function of neutrophil-T cell interactions in the regulation of vascularization at the maternal-fetal interface.
Assuntos
Neovascularização Fisiológica , Neutrófilos/citologia , Placenta/fisiologia , Linfócitos T Reguladores/citologia , Adulto , Animais , Decídua/fisiologia , Feminino , Proteína Forkhead Box O1/fisiologia , Técnicas de Silenciamento de Genes , Voluntários Saudáveis , Humanos , Sistema Imunitário , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fenótipo , Gravidez , Adulto JovemRESUMO
In a model of growth-restricted sheep pregnancy, it was previously demonstrated that transient uterine artery VEGF overexpression can improve fetal growth. This approach was tested in guinea-pig pregnancies, where placental physiology is more similar to humans. Fetal growth restriction (FGR) was attained through peri-conceptual nutrient restriction in virgin guinea pigs. Ad.VEGF-A165 or Ad.LacZ (1 × 1010vp) was applied at mid-gestation via laparotomy, delivered externally to the uterine circulation with thermosensitive gel. At short-term (3-8 days post surgery) or at term gestation, pups were weighed, and tissues were sampled for vector spread analysis, VEGF expression, and its downstream effects. Fetal weight at term was increased (88.01 ± 13.36 g; n = 26) in Ad.VEGF-A165-treated animals compared with Ad.LacZ-treated animals (85.52 ± 13.00 g; n = 19; p = 0.028). The brain, liver, and lung weight and crown rump length were significantly larger in short-term analyses, as well as VEGF expression in transduced tissues. At term, molecular analyses confirmed the presence of VEGF transgene in target tissues but not in fetal samples. Tissue histology analysis and blood biochemistry/hematological examination were comparable with controls. Uterine artery relaxation in Ad.VEGF-A165-treated dams was higher compared with Ad.LacZ-treated dams. Maternal uterine artery Ad.VEGF-A165 increases fetal growth velocity and term fetal weight in growth-restricted guinea-pig pregnancy.
Assuntos
Adenoviridae/genética , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/terapia , Peso Fetal/genética , Terapia Genética , Vetores Genéticos/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Feminino , Cobaias , Gravidez , Fluxo Sanguíneo RegionalRESUMO
Maternal endothelial dysfunction is one of the main features of pregnancy-induced hypertension (PIH). It is generally accepted that circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) reflect the state of the endothelium, its injury and/or repair possibilities. The objective of this study was to determine whether the CECs and EPCs numbers in the circulation of women with PIH reflect the presence of this pathology. Peripheral blood cells of PIH and normotensive pregnant women were labeled with specific monoclonal antibodies. For CECs evaluation, samples were labeled with anti-CD31 and anti-CD45 antibodies; for EPCs with anti-VEGFR2/KDR and anti-CD34 antibodies. Cells were quantified by flow cytometry. The levels of both CECs (CD31(+), CD45(-)) and EPCs (CD34(+), VEGFR2/KDR(+)) in the peripheral blood of women with PIH were significantly lower compared with those of control pregnant women with normal blood pressure level. Lowered accessibility of maternal CECs and EPCs may diminish general regenerative potential of the patient endothelia, contributing to PIH symptoms and to the risk of subsequent coronary and arterial disease.