Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several lines of evidence support the hypothesis that vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of pre-eclampsia (PE). VEGF is a key component in the regulation of vascular remodelling and the survival of cytotrophoblasts in the placenta. In this case-control study, we aimed to test whether VEGF genetic polymorphisms are associated with the risk of severe PE. We enrolled 84 nulliparous pregnant women with severe PE (PE group). Their VEGF G(+405)C and VEGF C(-2578)A genotypes were determined by PCR-restriction fragment length polymorphism (PCR-RFLP) from venous blood samples and were compared with the corresponding VEGF genotypes of 96 nulliparous patients with uncomplicated pregnancies (control group). Carriers of the VEGF(+405)G allele occurred less frequently in PE than in the control group [P = 0.039; adjusted odds ratio (aOR) = 0.28, range: 0.08-0.93]. Hypertension and proteinuria were diagnosed earlier (by 1.6 weeks and 1.9 weeks, respectively) in PE patients with VEGF(-2578)A only after adjustment of this association for risk factors of PE. Our results suggest that carriers of VEGF(+405)G allele have a decreased susceptibility to PE and that the progression of PE may be modified by the presence of VEGF(-2578)A allele. Nevertheless, the clinical significance of these findings remains to be determined.
Mol Hum Reprod 2006 Apr
PMID:Genetic polymorphisms of vascular endothelial growth factor in severe pre-eclampsia. 1651 14

The aim of this study was to investigate patterns of gene expression in placental samples from patients with preeclampsia (PE), persistent bilateral uterine artery notching (without PE), and normal controls. This study included placental tissue from nine women with PE, seven with uncomplicated pregnancies and five with bilateral uterine artery notching in Doppler velocimetry tracings. Human cDNA microarrays with 6500 transcripts/genes were used and the results verified with real-time PCR and in-situ hybridization. Multidimensional scaling method and random permutation technique demonstrated significant differences among the three groups examined. Within the 6.5K arrays, 6198 elements were unique cDNA clones representing 5952 unique UniGenes and 5695 unique LocusLinks. Multidimensional scaling plots showed 5000 genes that met our quality criteria; among these, 366 genes were significantly different in at least one comparison. Differences in three genes of interest were confirmed with real-time PCR and in-situ hybridization; acid phosphatase 5 was shown to be overexpressed in PE samples and calmodulin 2 and v-rel reticuloendotheliosis viral oncogene homolog A (RELA) were downregulated in PE and uterine artery notch placentas. In conclusion downregulation of RELA and calmodulin 2 might represent an attempt by the placenta to compensate for elevations in intracellular calcium, possibly caused by hypoxia and/or apoptosis, in both pregnancies with uterine artery notching and preeclampsia.
Mol Hum Reprod 2006 Mar
PMID:Gene expression profiling of human placentas from preeclamptic and normotensive pregnancies. 1655 80

Cannabis use in pregnancy is associated with a range of obstetrical conditions. The molecular mechanisms underlying these effects have not been elucidated but are attributed to the actions of delta-9-tetrahydrocannabinol (Delta9-THC). In this study, concentrations of Delta9-THC equivalent to those found in the serum of cannabis users, i.e. approximately 20 microM, inhibited proliferation and activated a restricted tight transcriptional programme in the BeWo trophoblast cell line. Employing genome-wide expression profiling methods, we found that the pattern of gene expression differs from that described in the placenta of patients with fetal growth restriction (FGR), associated with either hypoxia or discordant dichorionic twins, or of patients with pre-eclampsia. It was also dissimilar to the patterns obtained from the transcriptome of other tissues, such as the mouse brain, treated with Delta9-THC. The expression of transcription factors, such as thyroid hormone receptor-beta1 (TRbeta1), and transcriptional co-repressors, such as histone deactylase 3 (HDAC3), was affected by Delta9-THC in a dose-dependent manner, whereby 15 microM Delta9-THC caused a 2.8-fold inhibition of TRbeta1 expression, but a 3.5-fold increase in HDAC3 expression. These data were confirmed by end-point RT-PCR analyses and underpin the observed Delta9-THC-induced inhibition of BeWo cell proliferation. Genes encoding for growth, apoptosis, cell morphology and ion exchange pathways were modulated by 15 microM Delta9-THC. This study may provide insight into the mechanisms underlying the effects of Delta9-THC and cannabis use upon placental development during pregnancy.
Mol Hum Reprod 2006 May
PMID:Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. 1659 38

The placenta is central to foetal growth and development in mammalian pregnancy. Compromised placental function (as found in pre-eclampsia) often results in life-threatening situations for both mother and foetus. The nitric-oxide (NO) signalling cascade is important for placental function, in particular for the development of the vascular network and for maintaining vascular tone. This pathway seems to be regulated by multiple hormonal signals. Emerging evidence suggests that pathogenic mechanisms that are involved in abnormal placental function target specific molecules, such as hormone receptors, that regulate NO release and have subsequent dramatic consequences. Here, we discuss the current knowledge of NO function in the placenta, its hormonal regulation in normal pregnancy and in the pathophysiology of pre-eclampsia, its potential pathogenic mechanisms and possible use as a therapeutic target.
Trends Mol Med 2006 May
PMID:Hormonal regulation of placental nitric oxide and pathogenesis of pre-eclampsia. 1661 40

The pregnancy disorder pre-eclampsia (PE) is thought to be caused in part by shallow invasion of the extravillous trophoblast (EVT) leading to uteroplacental insufficiency and hypoxia. Here, we focused on the expressions of cysteine-rich 61 (CYR61, CCN1) and nephroblastoma overexpressed (NOV, CCN3), members of the CCN family of angiogenic regulators, in human placenta during normal pregnancy compared with pre-eclamptic and HELLP placentae using quantitative RT-PCR, western blotting and immunocytochemistry. During normal pregnancy, both proteins showed increasing expression levels and were strongly coexpressed in endothelial cells of vessels, stromal cells and interstitial EVT giant cells. However, NOV showed an earlier onset of expression in villous endothelial cells during gestation compared with CYR61, which may signify distinct roles of these proteins in placental angiogenesis. In early-onset pre-eclamptic placentae, both CYR61 and NOV were expressed at a significantly lower level compared with normal matched controls. This decrease of CYR61 and NOV in pre-eclamptic placentae is not associated with a decrease of the endothelial marker CD34 or vimentin. No obvious changes in the localization of CYR61 and NOV in pre-eclamptic placentae were detected but a change in the intracellular distribution in trophoblast giant cells. Our data point to a potential role of both molecules in the pathogenesis of early-onset PE.
Mol Hum Reprod 2006 Jun
PMID:Decreased expression of the angiogenic regulators CYR61 (CCN1) and NOV (CCN3) in human placenta is associated with pre-eclampsia. 1667 45

Elevated circulating levels of the tachykinin, neurokinin B (NKB), have been observed in women with pre-eclampsia during the third trimester of pregnancy. Currently, the molecular mechanisms responsible for these increased levels remain unknown. To understand the molecular regulation, we have compared the differences in gene expression of the tachykinins and their receptors in control and pre-eclamptic placentae and the responses of the TAC3 gene encoding NKB to proposed physiological triggers of pre-eclampsia including hypoxia and oxidative stress using real-time quantitative PCR. We have determined the placenta to be the main site of TAC3 expression with levels 2.6-fold higher than the brain. TAC3 expression was found to be significantly higher in pre-eclamptic placenta (1.7-fold, P < 0.05) than in normal controls. No evidence was found that hypoxia and oxidative stress were responsible for increases in TAC3 expression. In rat placenta, a longitudinal study in normal late pregnancy was associated with a significant down-regulation of the NKB/NK3 ligand-receptor pair (P < 0.05). The present data suggest that the increased placental expression of TAC3 is part of the mechanism leading to the increased circulating levels of NKB in pre-eclampsia.
Mol Hum Reprod 2006 Jul
PMID:Gene regulation of neurokinin B and its receptor NK3 in late pregnancy and pre-eclampsia. 1670 96

Pre-eclampsia/eclampsia (PE/E) is a common, serious medical disorder of human pregnancy. Familial association of PE/E has been recognized for decades, but the genetics are complex and poorly understood. In an attempt to identify PE/E susceptibility genes, we embarked on a positional cloning strategy using 34 Australian and New Zealand PE/E pedigrees. An initial 10-cM resolution genome scan revealed a putative susceptibility locus spanning a broad region on chromosome 2 that overlaps an independently determined linkage signal seen in Icelandic PE pedigrees. Subsequent fine mapping using 25 additional short tandem repeat (STR) markers in this region and non-parametric multipoint linkage analysis did not change the overall position. Under a strict diagnosis of PE, we obtained significant evidence of linkage on 2q with a peak log-of-odds ratio score (LOD) of 3.43 near marker D2S151 at 155 cM. To prioritize positional candidate genes at the 2q locus for detailed analysis, we applied an objective prioritization strategy that integrates quantitative bioinformatics, assessment of differential gene expression and association analysis of single-nucleotide polymorphisms (SNPs). Highest priority was assigned to the activin receptor gene ACVR2. This gene also showed >10-fold differential gene expression in human decidual tissue from normotensive and PE individuals. We genotyped five known SNPs in this gene in our pedigrees and performed tests for association and linkage disequilibrium. One SNP (rs1424954) showed strong preliminary evidence of association with PE (P = 0.007), whereas two others (rs1364658 and rs1895694) exhibited nominal evidence (P < 0.05). Haplotype analysis revealed no additional association information. There was evidence of weak linkage disequilibrium among these SNPs. The highest observed LD occurred between the two strongest associated SNPs, suggesting that the observed signals may be the signature of an observed functional variant.
Mol Hum Reprod 2006 Aug
PMID:Objective prioritization of positional candidate genes at a quantitative trait locus for pre-eclampsia on 2q22. 1680 77

Leptin, an adipocyte hormone involved in energy homeostasis, is important in reproduction and pregnancy. Questions yet to be addressed include the source of higher leptin during pregnancy and its relationship to pregnancy outcome and fetal growth. The objective of this study was to investigate the relationship between placental leptin gene expression, placental leptin protein concentration and maternal plasma leptin concentration among control pregnant women, women with pre-eclampsia and women with growth-restricted infants. We also investigated the relationship between placental leptin expression and the placental expression of enzymes involved in cellular lipid balance: fatty acid translocase (CD36), carnitine palmitoyltransferase I (CPT-1B) and lipoprotein lipase (LPL). Placental leptin expression, placental protein and maternal plasma concentration were higher in pre-eclampsia than in controls but not in women with growth-restricted infants. Placental leptin expression and placental protein were higher in the preterm pre-eclamptic subjects, whereas maternal leptin was higher in the term pre-eclamptic subjects. The placental gene expression of CD36, CPT-1B and LPL were not different among the groups. This study suggests that despite similar failed placental bed vascular remodelling in pre-eclampsia and intrauterine growth restriction (IUGR), leptin gene expression is higher only in preterm pre-eclampsia.
Mol Hum Reprod 2006 Sep
PMID:Relationships between maternal plasma leptin, placental leptin mRNA and protein in normal pregnancy, pre-eclampsia and intrauterine growth restriction without pre-eclampsia. 1687 Sep 54

In pregnant females, placenta is the most important source of lipid hydroperoxides and other reactive oxygen species (ROS). The increased production of lipid peroxides is often linked to preeclampsia. In our study, we revealed that NADPH- and iron-dependent lipid peroxidation in human placental microsomes (HPM) occurred. In the presence of Fe2+ ion, HPM produced small amounts of thiobarbituric acid-reactive substances (TBARS) - a final product of lipid peroxidation. NADPH caused a strong increase of iron stimulated TBARS formation. TBARS formation was inhibited by superoxide dismutase, butylated hydroxytoluene and alpha-tocopherol but not by mannitol or catalase. TBARS and superoxide radical production was inhibited in similar manner by cytochrome P450 inhibitors. The results obtained led us to the following conclusions: (1) microsomal lipid peroxidation next to mitochondrial lipid peroxidation may by an important source of lipid hydroperoxides in blood during pregnancy and (2) superoxide radical released by microsomal cytochrome P450 is an important factor in NADPH- and iron-dependent lipid peroxidation in HPM.
Mol Cell Biochem 2007 Jan
PMID:The NADPH- and iron-dependent lipid peroxidation in human placental microsomes. 1689 36

Peroxynitrite, a potent pro-oxidant formed from the interaction of superoxide and nitric oxide, has been widely reported to be nitrating tyrosine residues in proteins resulting in the formation of nitrotyrosine. Biological nitration of tyrosine, a footprint of oxidative injury, has been found to occur in various pathological states including pre-eclampsia, a leading cause of maternal mortality and increased perinatal mortality. Oxidative stress is a major contributor to endothelial dysfunction in pre-eclampsia. Previously, we have demonstrated increased nitrotyrosine immunostaining in placental villous vascular endothelium, surrounding vascular smooth muscle and villous stroma from pre-eclamptic or diabetic pregnancies. Immunoprecipitation (IP) with antinitrotyrosine antibodies followed by immunoblot analysis identified increased nitration of phospho-p38 mitogen-activated protein kinase (MAPK) in the pre-eclamptic placenta. The catalytic activity of p38 MAPK and concentration of phospho-p38 MAPK was also found to be reduced in placentae from pre-eclamptic pregnancies. Comparison of peptide masses of a 42-kDa protein obtained by mass spectrometry with masses of a theoretical tryptic digest of p38 MAPK that was modified by phosphorylation and nitration identified the protein to be p38 MAPK.
Mol Hum Reprod 2006 Nov
PMID:Nitration of p38 MAPK in the placenta: association of nitration with reduced catalytic activity of p38 MAPK in pre-eclampsia. 1695 26


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