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    ABSTRACT: We assessed whether placental morphology is affected by placental storage before fixation. Fresh tissue from uncomplicated pregnancies (n = 10) was fixed immediately and further samples were stored dry, in PBS or culture medium for 24, 48 or 72 h at 4 °C. Placental morphology quantified using image analysis software found no difference in syncytial nuclear aggregates, cytokeratin 7, CD45 or Ki67 immunostaining irrespective of duration or mode of storage. The number of blood vessels per villus (CD31) was reduced in all conditions after 72 h (p < 0.05). Distal villous hypoplasia increased after 72 h (p < 0.05). Ideally, storage time should be minimised to ≤48 h prior to morphological or qualitative analysis.
    Placenta 08/2013;
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    ABSTRACT: The potency of adult-derived circulating progenitor Endothelial Colony Forming Cells (ECFCs) is drastically surpassed by their fetal counterparts. Human pregnancy is associated with robust intensification of blood flow and vascular expansion in the uterus, crucial for placental perfusion and fetal supply. Here we investigate whether fetal ECFCs transmigrate to maternal bloodstream and home to locations of maternal vasculogenesis, primarily the pregnant uterus. In the first instance, endothelial-like cells, originating from mouse fetuses expressing paternal eGFP, were identified within uterine endothelia. Subsequently, LacZ or eGFP-labelled human fetal ECFCs, transplanted into immuno-deficient (NOD/SCID) fetuses on D15.5 pregnancy, showed similar integration into the mouse uterus by term. Mature endothelial controls (HUVECs), similarly introduced, were unequivocally absent. In humans, SRY was detected in 6/12 myometrial microvessels obtained from women delivering male babies. The copy number was calculated at 175 [IQR 149-471] fetal cells/mm(2) endothelium, constituting 12.5% of maternal vessel lumina. Cross-sections of similar human vessels, hybridized for Y-chromosome, positively identified endothelial-associated fetal cells. It appears that through ECFC donation, fetuses assist maternal uterine vascular expansion in pregnancy; potentiating placental perfusion and consequently their own fetal supply. In addition to fetal growth, this cellular mechanism holds implications for materno-fetal immune-interactions and long-term maternal vascular health.
    Stem Cells 04/2013;
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    ABSTRACT: Preeclampsia, a hypertensive pregnancy complication, is largely unpredictable in healthy nulliparous pregnant women. Accurate preeclampsia prediction in this population would transform antenatal care. To identify novel protein markers relevant to the prediction of preeclampsia, a 3-step mass spectrometric work flow was applied. On selection of candidate biomarkers, mostly from an unbiased discovery experiment (19 women), targeted quantitation was used to verify and validate candidate biomarkers in 2 independent cohorts from the SCOPE (SCreening fOr Pregnancy Endpoints) study. Candidate proteins were measured in plasma specimens collected at 19 to 21 weeks' gestation from 100 women who later developed preeclampsia and 200 women without preeclampsia recruited from Australia and New Zealand. Protein levels (n=25), age, and blood pressure were then analyzed using logistic regression to identify multimarker models (maximum 6 markers) that met predefined criteria: sensitivity ≥50% at 20% positive predictive value. These 44 algorithms were then tested in an independent European cohort (n=300) yielding 8 validated models. These 8 models detected 50% to 56% of preeclampsia cases in the training and validation sets; the detection rate for preterm preeclampsia cases was 80%. Validated models combine insulin-like growth factor acid labile subunit and soluble endoglin, supplemented with maximally 4 markers of placental growth factor, serine peptidase inhibitor Kunitz type 1, melanoma cell adhesion molecule, selenoprotein P, and blood pressure. Predictive performances were maintained when exchanging mass spectrometry measurements with ELISA measurements for insulin-like growth factor acid labile subunit. In conclusion, we demonstrated that biomarker combinations centered on insulin-like growth factor acid labile subunit have the potential to predict preeclampsia in healthy nulliparous women.
    Hypertension 04/2013;
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    ABSTRACT: Current therapies for preterm labour (PTL) focus on arresting myometrial contractions but are largely ineffective, thus alternative therapeutic targets need to be identified. Leukocytes infiltrate the uterus around the time of labour, and are in particularly abundant in decidua (maternal-fetal interface). Moreover, decidual inflammation precedes labour in rat pregnancies and thus may contribute to initiation of labour. We hypothesized that chemokines mediate decidual leukocyte trafficking during preterm labour (PTL) and term labour (TL), thus representing potential targets for preventing PTL. Women were recruited into 4 groups: TL, term not in labour (TNL), idiopathic PTL and PTL with infection (PTLI). Choriodecidual RNA was subjected to a pathway-specific PCR array for chemokines. Differential expression of 12 candidate chemokines was validated by real time RT-PCR and Bioplex assay, with immunohistochemistry to confirm cellular origin. 25 chemokines were upregulated in choriodecidua from TL compared to TNL. A similar pattern was detected in PTL, however a distinct profile was observed in PTLI consistent with differences in leukocyte infiltration. Upregulation of CCL2, CCL4, CCL5, CXCL8 and CXCL10 mRNA and protein was confirmed in TL, with CCL8 upregulated in PTL. Significant correlations were detected between these chemokines and decidual leukocyte abundance previously assessed by immunohistochemical and image analysis. Chemokines were primarily expressed by decidual stromal cells. In addition, CXCL8 and CCL5 were significantly elevated in maternal plasma during labour, suggesting chemokines contribute to peripheral inflammatory events during labour. Differences in chemokine expression patterns between TL and idiopathic PTL may be attributable to suppression of chemokine expression by betamethasone administered to women in PTL; this was supported by in vitro evidence of chemokine downregulation by clinically relevant concentrations of the steroid. The current study provides compelling evidence that chemokines regulate decidual leukocyte recruitment during labour. The 6 chemokines identified represent potential novel therapeutic targets to block PTL.
    PLoS ONE 02/2013; 8(2):e56946.
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    ABSTRACT: Adequate blood flow through placental chorionic plate resistance arteries (CPAs) is necessary for oxygen and nutrient transfer to the fetus and a successful pregnancy. In non-placental vascular smooth muscle cells (SMCs), K(+) channels regulate contraction, vascular tone and blood flow. Previous studies showed that K(+) channel modulators alter CPA tone, but did not distinguish between effects on K(+) channels in endothelial cells and SMCs. In this study, we developed a preparation of freshly isolated CPASMCs of normal pregnancy and investigated K(+) channel expression and function. CPASMCs were isolated from normal human term placentas using enzymatic digestion. Purity and phenotype was confirmed with immunocytochemistry. Whole-cell patch clamp was used to assess K(+) channel currents, and mRNA and protein expression was determined in intact CPAs and isolated SMCs with RT-PCR and immunostaining. Isolated SMCs expressed α-actin but not CD31, a marker of endothelial cells. CPASMCs and intact CPAs expressed h-caldesmon and non-muscle myosin heavy chain-2; phenotypic markers of contractile and synthetic SMCs respectively. Whole-cell currents were inhibited by 4-AP, TEA, charybdotoxin and iberiotoxin implicating functional K(v) and BK(Ca) channels. 1-EBIO enhanced whole cell currents which were abolished by TRAM-34 and reduced by apamin indicating activation of IK(Ca) and SK(Ca) respectively. BK(Ca), IK(Ca) and SK(Ca)3 mRNA and/or protein were expressed in CPASMCs and intact CPAs. This study provides the first direct evidence for functional K(v), BK(Ca,) IK(Ca) and SK(Ca) channels in CPASMCs. These cells display a mixed phenotype implicating a dual role for CPASMCs in controlling both fetoplacental vascular resistance and vasculogenesis.
    PLoS ONE 02/2013; 8(2):e57451.
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    ABSTRACT: Since their discovery, endothelial progenitor cells (EPCs) have generated considerable interest in vascular biology. They are a heterogeneous population of cells that exist in both the fetus and adult, and are mobilized to support de novo vessel formation or encourage vascular health. This review summarizes our understanding of these cells in pregnancy, paying particular attention to their physiological role in placental development and the uterus, alongside their involvement in related obstetric pathologies.
    Placenta 02/2013;
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    ABSTRACT: Taurine is an important nutrient in intrauterine life, being required for fetal organ development and cellular renewal of syncytiotrophoblast (STB), the nutrient transport epithelium of the placenta. As taurine is conditionally essential in human pregnancy, the fetal and placental demand for taurine is met by uptake from maternal blood into STB through the activity of TauT. Pre-eclampsia (PE) and maternal obesity are serious complications of pregnancy, associated with fetal growth restriction (FGR) and abnormal renewal of STB, and maternal obesity is a major risk factor for PE. Here we test the hypothesis that STB TauT activity is reduced in maternal obesity and PE compared to normal pregnancy.STB TauT activity, measured in fragments of placental tissue, was negatively related to maternal BMI over the range 18-46 kg/m(2) in both the first trimester (7-12 weeks gestation) and at term (p < 0.01; linear regression). Neither TauT activity nor expression in the first trimester differed to normal pregnancy at term. STB TauT activity was significantly lower in PE than normal pregnancy (p < 0.01). Neuropeptide Y (NPY), a protein kinase C (PKC) activator which is elevated in PE and obesity, reduced STB TauT activity by 20% (50 pM-50 nM: 2 h) (p < 0.03). Activation of PKC by phorbol 12-myristate-13-acetate (1 μM) reduced TauT activity by 18% (p < 0.05). As TauT activity is inhibited by phosphorylation, we propose that NPY activates PKC in the STB which phosphorylates TauT in PE and maternal obesity.Reduced TauT activity could contribute to dysregulated renewal of STB and FGR that are common to PE and maternal obesity.
    Advances in Experimental Medicine and Biology 01/2013; 776:81-91.
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    ABSTRACT: Abstract Background: Maternal obesity is a frequent obstetric risk factor, linked with short- and long-term consequences for mother and child, including fetal overgrowth, growth restriction and stillbirth. The mechanisms underlying these pathologies remain unknown but likely involve the placenta. Aims: To study placental cell turnover in relation to maternal body mass index (BMI). Methods: Term placental villous tissue was randomly sampled from 24 pregnancies, with a range of maternal BMI of 19.5-49.6. Immunohistochemistry was performed for hCG, Ki67 and M30 and image analysis used to calculate syncytiotrophoblast area and proliferative and apoptotic indices. Results were compared categorically between women of BMI 18.5-24.9 (normal), BMI 30.0-39.9 (obese class 1&2) and BMI 40+ (obese class 3), and continuously against BMI; p < 0.05 by Kruskal-Wallis test or linear regression was considered statistically significant. Results: Increased maternal BMI was associated with categorical (normal vs. obese class 3 and obese class 1&2 vs. obese class 3, both p < 0.05) and continuous (r(2) = 0.24, p = 0.016) reductions in the proliferative index and a continuous reduction (r(2) = 0.17, p = 0.047) in the apoptotic index. Discussion: Maternal obesity is associated with a dose-dependent reduction in placental villous proliferation and apoptosis which may increase susceptibility to adverse pregnancy outcomes.
    The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 12/2012;
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    ABSTRACT: Since the advent of technologies to produce genetic knockout and transgenic mice, the number of mouse strains suggested to be useful as models for pregnancy-related complications in the human has risen substantially. Some of these share features in common with fetal growth restriction (FGR) and preeclampsia (PE) and could be useful for investigating aetiologies and for testing potential therapeutics to improve outcome in these diseases. However, since placental pathology is a major underlying factor in both FGR and PE, it is important to understand the similarities and differences in structure and function of the placenta between mice and women. The main aim of this review is to directly compare placental exchange physiology between human and mouse. The review will compare human and mouse in both normal and pathological circumstances, to attempt to answer the question of whether placental studies in the mouse can be translated to the human. The review includes descriptions of placental structure between the species, comparisons of nutrient transport, including amino acids, glucose and calcium, and evidence of how these transport systems are altered in both human FGR and mouse models of this disease. Finally, our review will conclude by examining studies in which mouse models of FGR/PE have been treated with drugs of potential therapeutic value in women and consider whether data obtained in mice can be a prelude for clinical trials in human.
    Placenta 11/2012;
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    ABSTRACT: We tested the hypothesis that crossing two mouse models of fetal growth restriction (FGR) of differing phenotype would induce more severe FGR than either model alone. Female endothelial nitric oxide synthase knockout mice (eNOS(-/-)) were mated with placental-specific Igf2 knockout males (P0). Resultant fetuses were no more growth restricted than those with P0 deletion alone. However, P0 deletion attenuated the reduced placental system A amino acid transporter activity previously observed in eNOS(-/-) mice. Manipulating maternal and fetal genotypes provides a means to compare maternal and fetal regulation of fetal growth.
    Placenta 10/2012;
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