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1.  First trimester uric acid and adverse pregnancy outcomes 
American journal of hypertension  2011;24(4):489-495.
BACKGROUND
The association of elevated serum uric acid with the development of hypertension is established outside of pregnancy. We investigated whether first trimester uric acid was associated with the development of the following: gestational hypertension or preeclampsia, these outcomes stratified by presence of hyperuricemia at delivery since this denotes more severe disease, preterm birth or small for gestational age (SGA).
METHODS
Uric acid was measured in 1541 banked maternal plasma samples from a prior prospective cohort study that were collected at a mean gestational age of 9.0 (± 2.5) weeks. Polytomous regressions were performed and adjusted for parity and pre-pregnancy body mass index.
RESULTS
First trimester uric acid in the highest quartile (>3.56 mg/dL) compared to lowest three quartiles was associated with an increased risk of developing preeclampsia (adjusted OR = 1.82; 95% CI, 1.03–3.21) but not gestational hypertension. In women with hypertensive disease complicated by hyperuricemia at delivery, high first trimester uric acid was associated with a 3.22-fold increased risk of hyperuricemic gestational hypertension and a 3.65-fold increased risk of hyperuricemic preeclampsia. High first trimester uric acid was not associated with gestational hypertension or preeclampsia without hyperuricemia at delivery, preterm birth, or SGA. In women who developed hypertensive disease, elevated uric acid at delivery was only partly explained by elevated uric acid in the first trimester (r2 = .23).
CONCLUSIONS
First trimester elevated uric acid was associated with later preeclampsia and more strongly with preeclampsia and gestational hypertension with hyperuricemia.
doi:10.1038/ajh.2010.262
PMCID: PMC3062659  PMID: 21252861
gestational hypertension; hyperuricemia; preeclampsia; uric acid
2.  Human Placental Adenosine Receptor Expression is Elevated in Preeclampsia and Hypoxia Increases Expression of the A2A Receptor 
Placenta  2009;30(5):434-442.
Placental hypoxia as a result of impaired trophoblast invasion is suggested to be involved in the pathophysiology of preeclampsia. Hypoxia is a potent stimulus for the release of adenosine, and the actions of adenosine are mediated through four adenosine receptors, A1, A2A, A2B and A3. We investigated the presence, distribution and expression of adenosine receptor subtypes in the human placenta, the expression of the adenosine receptors in placentas from pregnancies complicated by preeclampsia, small for gestational age (SGA) infants and uncomplicated pregnancies, and the effect of hypoxia on placental adenosine receptor expression. Immunofluorescent microscopy localized A1, A2A, A2B and A3 adenosine receptors to the syncytiotrophoblast, endothelial cells and myo-/fibroblasts within the human placenta. Adenosine receptor protein and message expression levels were significantly higher in placentas from preeclamptic pregnancies with or without SGA infants, but not different in pregnancies with SGA infants alone. In vitro exposure of placental villous explants to hypoxia (2% oxygen) increased the expression of A2A adenosine receptor 50%. These data indicate that all four known adenosine receptors are expressed in the human placenta and adenosine receptor expression is significantly higher in pregnancies complicated by preeclampsia. These data are consistent with the hypothesis that differences in placental adenosine receptors may contribute to alterations in placental function in preeclampsia.
doi:10.1016/j.placenta.2009.02.004
PMCID: PMC2674514  PMID: 19303140
3.  Leptin Affects System A Amino Acid Transport Activity in the Human Placenta: Evidence for STAT3 Dependent Mechanisms 
Placenta  2009;30(4):361-367.
Background:
Amino acids are important nutrients during fetal development, and the activity of placental amino acid transporters is crucial in the regulation of fetal growth. Leptin, an adipocyte- and placenta-derived hormone, has been proposed to act as a peripheral signal in reproduction in humans. Leptin is elevated during pregnancy and elevated further in pathologic pregnancies such as preeclampsia. However, the role of leptin in placental function has not been fully elucidated. We hypothesize that leptin plays a role in the regulation of placental amino acid transport by activation of the JAK-STAT pathway.
Methods:
Placental amino acid transport, specifically system A transport was studied in placental villous fragments using the amino acid analog, methylaminoisobutyric acid (MeAIB). Specific inhibitors of the JAK-STAT signal transduction pathway were used to further elucidate their role in leptin-mediated effects on amino acid transport activity. Western blotting was performed to identify STAT3 phosphorylation as a measure of leptin receptor activation.
Results:
Leptin significantly increased system A amino acid transporter activity by 22-42% after 1 h of incubation. Leptin activated JAK-STAT signaling pathway as evidenced by STAT3 phosphorylation, and inhibition of STAT3 or JAK2 resulted in 36-45% reduction in system A amino acid transporter activity. Furthermore, blocking endogenously produced leptin also decreased system A transport by 45% comparable to STAT3 inhibition.
Conclusions:
These data demonstrate that leptin stimulates system A by JAK-STAT dependent pathway in placental villous fragments. Our findings support the autocrine/paracrine role of leptin in regulating amino acid transport in the human placenta.
doi:10.1016/j.placenta.2009.01.004
PMCID: PMC2675556  PMID: 19203792
4.  Novel Soluble Flt-1 Isoforms in Plasma and Cultured Placental Explants from Normotensive Pregnant and Preeclamptic Women 
Placenta  2008;30(1):25-34.
Pregnant women who develop preeclampsia exhibit higher circulating levels of the soluble VEGF receptor-1 (sFlt-1). Recent findings suggest that soluble Flt-1 may contribute to the pathogenesis of preeclampsia by binding and neutralizing vascular endothelial growth factors (VEGF) and placental growth factor (PlGF). Existing literature identifies sFlt-1 as a 100 kDa glycoprotein, a product of an mRNA splice variant. We hypothesized that sFlt-1 expression may be more complex with multiple variants of sFlt-1 as well as multiple sources during normal pregnancy and preeclampsia. Using a combination of affinity purification of sFlt-1 by heparin-agarose and epitope specific antibodies, we performed Western blot analysis with epitope specific antibodies for sFlt-1. Plasma of preeclamptic women exhibits significantly higher amounts of a novel 145 kDa variant of sFlt-1, along with the 100 kDa isoform. We identified sFlt-1 variants in the conditioned medium from placental explant cultures that are hypoxia responsive with varying sizes, including 185, 145,100 and 60 kDa forms, as well as antigenicity. The 145 kDa was similar in antigenicity to the 100 kDa found in plasma whereas the 185 and 60 kDa sFlt-1 demonstrated different epitopes. Deglycosylation studies also confirm that there are multiple sFlt-1 polypeptides. Co-immunoprecipitation with VEGF suggests that these different sFlt isoforms can bind VEGF and therefore, may be of functional importance. Finally, comparison of sFlt-1 in the conditioned medium obtained from cultured cytotrophoblasts, peripheral blood mononuclear cells (PBMCs) and human uterine microvascular cells (HUtMVECs) exhibit mainly the100 kDa sFlt-1. Collectively these data suggest the presence of multiple isoforms of sFlt-1 in the circulation of women with preeclampsia as well as in uncomplicated pregnancies and the possibility of multiple sources. Placental hypoxia may contribute to sFlt-1 over expression but other regulatory mechanisms cannot be ruled out.
doi:10.1016/j.placenta.2008.10.006
PMCID: PMC2607481  PMID: 19010535
Villous explant culture; Conditioned medium; Preeclampsia; Plasma; Heparin-agarose; New soluble Flt-1 variants; sFlt-1; Deglycosylation; VEGF binding
5.  Placental System A Amino Acid Transport is Reduced in Pregnancies With Small For Gestational Age (SGA) Infants but Not in Preeclampsia with SGA Infants 
Placenta  2008;29(10):879-882.
Preeclampsia and intrauterine growth restriction (IUGR) are both associated with abnormal remodeling of maternal spiral arteries perfusing the placental site. This would be expected to be associated with reduced fetal growth, yet only one third of infants of mothers with preeclampsia are growth restricted. Infants with IUGR have decreased concentrations of amino acids in their blood and system A amino acid transporter activity is reduced in their placentas. Since infants of preeclamptic pregnancies have increased circulating amino acids, we tested system A amino acid transport activity of placental villous fragments from pregnancies with small for gestational age (SGA) infants with and without maternal preeclampsia and from uncomplicated and preeclamptic pregnancies with normal sized infants. We confirm the reduced uptake of amino acids in SGA pregnancies without preeclampsia but report that placental amino acid uptake of SGA infants with maternal preeclampsia is not reduced and is identical to uptake by normal and preeclamptic pregnancies with normal weight infants.
doi:10.1016/j.placenta.2008.07.001
PMCID: PMC2703008  PMID: 18718657
Placental transport; Amino acid; Preeclampsia; Intrauterine growth restriction

Results 1-5 (5)