11beta-Hydroxysteroid dehydrogenase type 2 in pregnancy and preeclampsia

Cortisol availability is controlled by 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which inactivates cortisol in cortisone, unable to bind to the glucocorticoid receptor. The 11beta-HSD2 enzyme activity limits either intracellular cortisol concentrations or within the uteroplacental compartment the transfer of cortisol into the fetal circulation. Mechanisms, by which 11beta-HSD2 activity is controlled, include transcriptional control, posttranscriptional modifications of 11beta-HSD2 transcript half-life, epigenetic regulation via methylation of genomic DNA and direct inhibition of enzymatic activity. The 11beta-HSD2 expression and activity is reduced in preeclampsia and the enzyme activity correlates with factors associated with increased vasoconstriction, such as an increased angiotensin II receptor subtype 1 expression, and notably fetal growth. Numerous signals such as proinflammatory cytokines known to be present and/or elevated in preeclampsia regulate 11beta-HSD2 activity. Shallow trophoblast invasion with the resulting hypoxemia seems to critically reduce available 11beta-HSD2 activity. A positive feedback exists as activated glucocorticoid receptors do enhance 11beta-HSD2 mRNA transcription and mRNA stability. No data are currently available on pregnancy and either epigenetic or direct effects on the activity of the translated enzyme.

Role of aldosterone availability in preeclampsia

Preeclampsia is a hypertensive disorder unique to pregnancy and remains the leading cause of maternal and fetal morbidity and mortality. Despite active research, the etiology of this disease remains still an enigma. There is increasing evidence that a combination of several factors is responsible for the development of preeclampsia. In this review, we discuss the role of aldosterone in the regulation of body fluid in pregnancy and preeclampsia. Aldosterone is produced by the enzyme aldosterone synthase and competes with cortisol and progesterone for the mineralocorticoid receptor, thus affecting sodium reabsorption and maternal volume expansion. Aldosterone seems to play a pivotal role in controlling blood pressure during pregnancy and to contribute to the well-being of the mother-to-be. Novel findings in understanding the underlying causes of preeclampsia provide a rationale for future novel prophylactic and therapeutic interventions in the treatment of this pregnancy-associated disease.

First-trimester serum levels of soluble endoglin and soluble fms-like tyrosine kinase-1 as first-trimester markers for late-onset preeclampsia

OBJECTIVE: The aim of this investigation was to assess soluble endoglin (sEng) and soluble fms-like tyrosine kinase-1 (sFlt1) as first-trimester serum markers to predict preeclampsia. STUDY DESIGN: First-trimester sera were obtained from 46 women with subsequent late-onset preeclampsia and from 92 controls. sEng and sFlt1 concentrations were determined immunoanalytically. Correlation analysis with inhibin A and placental growth factor levels was performed. RESULTS: sEng and sFlt1 serum concentrations were higher in women with subsequent preeclampsia than in controls (mean +/- SD, sEng: 5.57 +/- 1.18 ng/mL vs 5.02 +/- 1.01 ng/mL, P = .009; sFlt1: 1764 +/- 757 pg/mL vs 1537 +/- 812 pg/mL, P = .036). Sensitivities and specificities for predicting preeclampsia were 63% and 57% for sEng and 64% and 56% for sFlt1, respectively. When sEng and inhibin A were combined, the sensitivity increased to 68%, whereas the specificity was 61%. CONCLUSION: sEng and sFlt1 are increased in the first trimester in women with subsequent late-onset preeclampsia and might therefore prove useful to predict preeclampsia.

Prematurity is related to high placental cortisol in preeclampsia

Fetal growth is compromised in animal models with high cortisol availability. In healthy pregnancies, the fetus is protected from high circulating cortisol levels by the placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which is reduced in preeclampsia. We hypothesized increased placental cortisol availability in preeclampsia as missing link to fetal growth restriction and prematurity. Placental tissue was obtained from 39 pregnant women dichotomized normotensive (n = 16) or preeclamptic (n = 23). Placental steroid hormone metabolites were analyzed by gas chromatography-mass spectrometry. Apparent 11beta-HSD2 enzyme activity was calculated as substrate to product ratio. Estradiol and pregnandiol positively correlated with gestational age. Cortisol was virtually absent in 93.8% of controls, yet detectable in 79.3% of preeclamptic samples resulting in an odds ratio (OR) of 0.019 (95% CI 0.002-0.185) for the presence of placental cortisol. Apparent 11beta-HSD2 activity directly correlated with birth weight (R2 = 0.16; p < 0.02) and gestational age (R2 = 0.11; p < 0.04) ensuing a reduced risk of premature delivery (OR 0.12; 95% CI 0.02-0.58). We conclude that normotensive pregnancies are characterized by an almost completely inactivated placental cortisol. In line with our hypothesis, reduced 11beta-HSD2 activity in preeclampsia is unable to abolish placental cortisol, a finding clearly associated with prematurity and low birth weight.

Angiotensin receptor agonistic autoantibody is highly prevalent in preeclampsia: correlation with disease severity.

Preeclampsia (PE), a syndrome affecting 5% of pregnancies, characterized by hypertension and proteinuria, is a leading cause of maternal and fetal morbidity and mortality. The condition is often accompanied by the presence of a circulating maternal autoantibody, the angiotensin II type I receptor agonistic autoantibody (AT(1)-AA). However, the prevalence of AT(1)-AA in PE remains unknown, and the correlation of AT(1)-AA titers with the severity of the disease remains undetermined. We used a sensitive and high-throughput luciferase bioassay to detect AT(1)-AA levels in the serum of 30 normal, 37 preeclamptic (10 mild and 27 severe), and 23 gestational hypertensive individuals. Here we report that AT(1)-AA is highly prevalent in PE ( approximately 95%). Next, by comparing the levels of AT(1)-AA among women with mild and severe PE, we found that the titer of AT(1)-AA is proportional to the severity of the disease. Intriguingly, among severe preeclamptic patients, we discovered that the titer of AT(1)-AA is significantly correlated with the clinical features of PE: systolic blood pressure (r=0.56), proteinuria (r=0.70), and soluble fms-like tyrosine kinase-1 level (r=0.71), respectively. Notably, only AT(1)-AA, and not soluble fms-like tyrosine kinase-1, levels are elevated in gestational hypertensive patients. These data serve as compelling clinical evidence that AT(1)-AA is highly prevalent in PE, and its titer is strongly correlated to the severity of the disease.

The detrimental role of angiotensin receptor agonistic autoantibodies in intrauterine growth restriction seen in preeclampsia.

Growth-restricted fetuses are at risk for a variety of lifelong medical conditions. Preeclampsia, a life-threatening hypertensive disorder of pregnancy, is associated with fetuses who suffer from intrauterine growth restriction (IUGR). Recently, emerging evidence indicates that preeclamptic women harbor AT(1) receptor agonistic autoantibodies (AT(1)-AAs) that contribute to the disease features. However, the exact role of AT(1)-AAs in IUGR and the underlying mechanisms have not been identified. We report that these autoantibodies are present in the cord blood of women with preeclampsia and retain the ability to activate AT(1) receptors. Using an autoantibody-induced animal model of preeclampsia, we show that AT(1)-AAs cross the mouse placenta, enter fetal circulation, and lead to small fetuses with organ growth retardation. AT(1)-AAs also induce apoptosis in the placentas of pregnant mice, human villous explants, and human trophoblast cells. Finally, autoantibody-induced IUGR and placental apoptosis are diminished by either losartan or an autoantibody-neutralizing peptide. Thus, these studies identify AT(1)-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta and entering fetal circulation, and indirectly through AT(1)-AA-induced placental damage. Our findings highlight AT(1)-AAs as important therapeutic targets.

Preeclampsia enhances neuroglial marker expression in umbilical cord Wharton's jelly-derived mesenchymal stem cells.

Objective: The aim of the study was to compare the neuroglial phenotype of Wharton's jelly-derived mesenchymal stem cells (WJ-MSC) from pregnancies complicated with preeclampsia and gestational age (GA)-matched controls. Methods: WJ-MSC were isolated from umbilical cords from both groups and analyzed for the cell surface expression of MSC markers and the gene and protein expression of neuroglial markers. Results: All WJ cells were highly positive for the MSC markers CD105, CD90 and CD73, but negative for markers specific for hematopoietic (CD34) and immunological cells (CD45, CD14, CD19 and HLA-DR). WJ-MSC from both groups expressed neuroglial markers (MAP-2, GFAP, MBP, Musashi-1 and Nestin) at the mRNA and protein level. The protein expressions of neuronal (MAP-2) and oligodendrocytic (MBP) markers were significantly increased in WJ-MSC from preeclampsia versus GA-matched controls. Conclusions: WJ-MSC from preeclamptic patients are possibly more committed to neuroglial differentiation through the activation of pathways involved both in the pathophysiology of the disease and in neurogenesis.

Is preeclampsia associated with restless legs syndrome?

OBJECTIVE Restless legs syndrome (RLS) is a common neurologic disorder. Secondary RLS includes pregnancy and iron deficiency. Prevalence of RLS in pregnancy ranges from 11% to 27%. We aimed to assess the frequency and characteristics of RLS in pregnancy in a Peruvian population and to evaluate the possible pregnancy or delivery complications due to RLS. METHODS We assessed 218 consecutive expectant mothers at the inpatient clinic of the Hospital San Bartolome in Lima, Peru. Assessment was performed by using the standard diagnostic criteria for RLS and by using a clinical and diagnostic interview. Questionnaires for RLS severity, idiopathic RLS (IRLS), and excessive daytime sleepiness (EDS) according to the Epworth sleepiness scale (ESS) were used. Blood examination was performed for hemoglobin and hematocrit. For comparison, RLS patients were matched for age and body mass index (BMI) with pregnant women without RLS. RESULTS Out of 218 patients, 40 (18.4%) fulfilled diagnostic criteria for RLS. In RLS patients, prophylactic iron supplementation therapy during pregnancy was less frequently taken (P=.02). Pregnant women with RLS had a higher ESS score than pregnant controls (10.6 +/- 3.1 vs 7.6. +/- 3.6; P<.001). Preeclampsia was more frequent in RLS (7/40 vs 1/39; P=.03). CONCLUSIONS In our study, RLS was frequent in pregnant Peruvian women, especially in those without prophylactic iron supplementation. RLS patients described more EDS. Preeclampsia was more common in RLS. Our study is the first study to indicate a possible association between RLS and preeclampsia.

Hypoxic treatment of human dual placental perfusion induces a preeclampsia-like inflammatory response.

Preeclampsia is a human pregnancy-specific disorder characterized by a placental pro-inflammatory response in combination with an imbalance of angiogenic factors and clinical symptoms, including hypertension and proteinuria. Insufficient uteroplacental oxygenation in preeclampsia due to impaired trophoblast invasion during placentation is believed to be responsible for many of the molecular events leading to the clinical manifestations of this disease. We investigated the use of hypoxic treatment of the dual placental perfusion system as a model for preeclampsia. A modified perfusion technique allowed us to achieve a mean soluble oxygen tension within the intervillous space (IVS) of 5-7% for normoxia and <3% for hypoxia (as a model for preeclampsia). We assayed for the levels of different inflammatory cytokines, oxidative stress markers, as well as other factors, such as endothelin (ET)-1 that are known to be implicated as part of the inflammatory response in preeclampsia. Our results show a significant increase under hypoxia in the levels of different inflammatory cytokines, including IL-6 (P=0.002), IL-8 (P<0.0001), TNF-α (P=0.032) and IFN-γ (P=0.009) at 360 min in maternal venous samples (n=6). There was also a significant increase in ET-1 levels under hypoxia both on the maternal side at 30 min (P=0.003) and fetal side at 360 min (P=0.036) (n=6). Other markers of oxidative stress, including malondialdehyde and 8-iso-protaglandin F2α (P=0.009) also show increased levels. Overall, these findings indicate that exposure of ex vivo dually perfused placental tissue to hypoxia provides a useful model for mimicking the inflammatory response characteristic of preeclampsia. This would therefore provide a powerful tool for studying and further delineating the molecular mechanisms involved in the underlying pathophysiology of preeclampsia.

PLACENTAL GLUCOSE TRANSPORTER (GLUT)-1 REGULATION IN PREECLAMPSIA

PLACENTAL GLUCOSE TRANSPORTER (GLUT)-1 REGULATION IN PREECLAMPSIA Camilla Marini a,b, Benjamin P. Lüscher a,b, Marianne J€orger-Messerli a,b, Ruth Sager a,b, Xiao Huang c, Jürg Gertsch c, Matthias A. Hediger c, Christiane Albrecht c, Marc U. Baumann a,c, Daniel V. Surbek a,c a Department of Obstetrics and Gynecology, University Hospital of Bern, Bern, Switzerland, Switzerland; b Department of Clinical Research, University of Bern, Bern, Switzerland, Switzerland; c Institute for Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland, Switzerland Objectives: Glucose is a primary energy source for the fetus. The absence of significant gluconeogenesis in the fetus means that the fetal up-take of this vital nutrient is dependent on maternal supply and subsequent transplacental transport. Altered expression and/or function of placental transporters may affect the intrauterine environment and could compromise fetal and mother well-being. We speculated that pre-eclampsia (PE) impairs the placental glucose transport system. Methods: Placentae were obtained after elective caesarean sections following normal pregnancies and pre-eclamptic pregnancies. Syncytial basal membrane (BM) and apical microvillus membrane (MVM) fractions were prepared using differential ultra-centrifugation and magnesium precipitation. Protein expression was assessed by western blot analysis. mRNA levels in whole villous tissue lysate were quantified by real-time PCR. To assess glucose transport activity a radiolabeled substrate up-take assay and a transepithelial transport model using primary cytotrophoblasts were established. Results: GLUT1 mRNA expression was not changed in PE when compared to control, whereas protein expression was significantly down-regulated. Glucose up-take into syncytial microvesicles was reduced in PE compared to control. In a transepithelial transport model, phloretinmediated inhibition of GLUT1 at the apical side of primary cytotrophoblasts showed a 44% of reduction of transepithelial glucose transport at IC50. Conclusions: GLUT1 is down-regulated on protein and functional level in PE compared to control. Altering glucose transport activity by inhibition of apical GLUT-1 indicates that transplacental glucose transport might be regulated on the apical side of the syncytiotrophoblast. These results might help to understand better the regulation of GLUT1 transporter and maybe in future to develop preventive strategies to modulate the fetal programming and thereby reduce the incidence of disease for both the mother and her child later in life.