Abstract-The recent discovery of additional alternative spliced FLT1 transcripts encoding novel soluble (s)FLT1 protein isoforms complicates both the predictive value and functional implications of sFLT1 in preeclampsia. We investigated FLT1 expression levels and splicing patterns in placentas of normotensive and preeclamptic women, and established the tissue specificity of all FLT1 transcript variants. mRNA levels of sFLT1 splice variants were determined by real-time polymerase chain reaction in 21 normal human tissues and placental biopsies from 91 normotensive and 55 preeclamptic women. Cellular localization of placental FLT1 expression was established by RNA in situ hybridization. Of all tissues investigated, placenta has by far the highest FLT1 mRNA expression level, mainly localized in the syncytiotrophoblast layer. More than 80% of placental transcripts correspond to sFLT1_v2. Compared with normotensive placenta, preeclamptic placenta has Ϸ3-fold higher expression of all FLT1 transcript variants (PϽ0.001), with a slight shift in favor of sFLT1_v1. Although to a lesser degree, transcript levels are also increased in placenta from normotensive women that deliver a small for gestational age neonate. We conclude that sFLT isoform-specific assays could potentially improve the accuracy of current sFLT1 assays for the prediction of preeclampsia. However, placental FLT1 transcript levels are increased not only in preeclampsia but also in normotensive pregnancy with a small for gestational age fetus. This may indicate a common pathway involved in the development of both conditions but complicates the use of circulating sFLT1 protein levels for the prediction or diagnosis of preeclampsia alone. (Hypertension. 2011;58:70-76.) • Online Data SupplementKey Words: endothelial growth factors Ⅲ gene expression Ⅲ human Ⅲ preeclampsia Ⅲ pregnancy H ypertension-related disorders are a major cause of pregnancy complications. Preeclampsia in particular, defined as new-onset hypertension in combination with proteinuria after 20 weeks of gestation, is a leading cause of both maternal and fetal mortality and morbidity. 1 Because preeclampsia is a complex disease involving multiple organs, it has been difficult to clearly assign molecular pathways involved in the etiology. Consequently, proper targets for the development of early biomarkers and prophylaxis are scarce.Although the exact model how preeclampsia develops is still a matter of debate, preeclampsia is thought to originate from abnormal placentation followed by a release of placenta-produced factors into the maternal circulation. These in turn provoke dysfunction of the maternal endothelium, resulting in the preeclamptic clinical symptoms. 2,3 The vascular endothelial growth factor (VEGF) ligands/receptors play an essential role in both normal and pathological functioning of the endothelium 4 and have been implicated in the development of preeclampsia. In particular, the soluble truncated version of VEGF receptor 1 (sFLT1) has been shown to be markedly elevated in preecla...
BackgroundPreterm delivery is the leading cause of neonatal morbidity and mortality. Two-thirds of preterm deliveries are idiopathic. The initiating molecular mechanisms behind spontaneous preterm delivery are unclear. Umbilical cord blood DNA samples are an easy source of material to study the neonatal state at birth. DNA methylation changes can be exploited as markers to identify spontaneous preterm delivery. To identify methylation differences specific to idiopathic preterm delivery, we assessed genome-wide DNA methylation changes in 24 umbilical cord blood samples (UCB) using the 450 K Illumina methylation array. After quality control, conclusions were based on 11 term and 11 idiopathic preterm born neonates. The differentially methylated positions (DMPs) specific for preterm/term delivery, neonatal sex, use of oxytocin and mode of initiation of labor were calculated by controlling the FDR p value at 0.05.ResultsThe analysis identifies 1855 statistically significant DMPs between preterm and term deliveries of which 508 DMPs are also attributable to clinical variables other than preterm versus term delivery.1347 DMPs are unique to term vs preterm delivery, of which 196 DMPs do not relate to gestational age as such. Pathway analysis indicated enrichment of genes involved in calcium signalling, myometrial contraction and relaxation pathways. The 1151 DMPs that correlate with advancing gestational age (p < 0.05) include 161 DMPs that match with two previously reported studies on UCB methylation.Additionally, 123 neonatal sex specific DMPs, 97 DMPs specific to the induction of labour and 42 DMPs specific to the mode of initiation of labor were also identified.ConclusionThis study identifies 196 DMPs in UCB DNA of neonates which do not relate to gestational age or any other clinical variable recorded and are specific to idiopathic preterm delivery. Furthermore, 161 DMPs from our study overlap with previously reported studies of which a subset is also reported to be differentially methylated at 18 years of age. A DMP on MYL4, encoding myosin light chain 4, is a robust candidate for the identification of idiopathic preterm labour as it is identified by all 3 independent studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1915-4) contains supplementary material, which is available to authorized users.
Protocols were in accord with institutional guidelines and were approved by the local institutional review board. All participants gave written informed consent. Consecutive, self-defined white and African-Dutch women undergoing an abdominal procedure for fibroid enucleation or hysterectomy for fibroids were eligible for inclusion.Abstract-Hypertension remains the main risk factor for cardiovascular death. Environmental and biological factors are known to contribute to the condition, and circulating creatine kinase was reported to be the main predictor of blood pressure in the general population. This was proposed to be because of high resistance artery creatine kinase-BB rapidly regenerating ATP for vascular contractility. Therefore, we assessed whether creatine kinase isoenzyme mRNA levels in human resistance arteries are associated with blood pressure. We isolated resistance-sized arteries from omental fat donated by consecutive women undergoing uterine fibroid surgery. Blood pressure was measured in the sitting position. Vessels of 13 women were included, 6 normotensive and 7 hypertensive, mean age 42.9 years (SE, 1.6) and mean systolic/ diastolic blood pressure, 144.8 (8.0)/86.5 (4.3) mm Hg. Arteriolar creatine kinase isoenzyme mRNA was assessed using quantitative real-time polymerase chain reaction. Normalized creatine kinase B mRNA copy numbers, ranging from 5.2 to 24.4 (mean, 15.0; SE, 1.9), showed a near-perfect correlation with diastolic blood pressure (correlation coefficient, 0.9; 95% confidence interval, 0.6-1.0) and were well correlated with systolic blood pressure, with a 90% relative increase in resistance artery creatine kinase B mRNA in hypertensives compared with normotensives, normalized copy numbers were, respectively, 19.3 (SE, 2.0) versus 10.1 (SE, 2.1), P=0.0045. To our knowledge, this is the first direct evidence suggesting that resistance artery creatine kinase mRNA expression levels concur with blood pressure levels, almost doubling with hypertension. These findings add to the evidence that creatine kinase might be involved in the vasculature's pressor responses. (Hypertension. 2014;63:68-73.)
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