M Cervar-Zivkovic

Complex expression changes of the placental endothelin system in early and late onset preeclampsia, fetal growth restriction and gestational diabetes

AIMS Preeclampsia (PE), fetal growth restriction (FGR) and gestational diabetes mellitus (GDM) are major pregnancy complications affecting maternal and fetal health. The placenta and the vasoconstrictor endothelin-1 (ET-1) have a controlling and mediating role in these conditions. This study tested the hypothesis that the expression of ET-1 and its receptors (ET(A) and ET(B)) is altered in these pathologies and differs between early (gestational week [GW] ≤ 34) and late (GW > 34) third trimester pregnancies. MAIN METHODS The study included 88 women (GW 28-41) with PE (blood pressure >140/90 mmHg, protein >300 mg/24 hrs; n=14), FGR (<10th birthweight centile and pathological umbilical blood flow; n=13), PE+FGR (n=5) and GDM (n=21), and gestational age-matched controls (n=35). ET-1, ET(A) and ET(B) mRNA and ET(A) and ET(B) protein were quantified in placental tissues by real-time PCR and immunoblotting. KEY FINDINGS The ET/ETR mRNA system is altered in PE and PE+FGR and GDM. Expression of ET-1, ET(A) and ET(B) is upregulated in early onset PE and PE+FGR with stronger effect in PE+FGR. GDM down regulated ET/ETR mRNA in the placentas in late third trimester of pregnancy. ET/ETR protein is virtually unchanged. SIGNIFICANCE Early onset PE (≤GW34) with or without FGR is associated with increased mRNA expression of the ET/ETR system, while in late onset PE and GDM the opposite effect was observed. This study supports the emerging concept that early and late onset PE are different diseases.

Placental Fractalkine Is Up-Regulated in Severe Early-Onset Preeclampsia

The pathogenesis of preeclampsia (PE) includes the release of placental factors into the maternal circulation, inducing an inflammatory environment in the mother. One of the factors may be the proinflammatory chemokine fractalkine, which is expressed in the syncytiotrophoblast of human placenta, from where it is released into the maternal circulation by constitutive shedding. We examined whether placental fractalkine is up-regulated in severe early-onset PE and whether the proinflammatory cytokines tumor necrosis factor (TNF)-α and IL-6 are able to increase the expression of fractalkine. Gene expression analysis, enzyme-linked immunosorbent assay, and immunohistochemistry consistently showed increased fractalkine expression in placentas from severe early-onset PE, compared to gestational age-matched controls. Expression of a disintegrin and metalloproteinases (ADAMs) 10 and 17, which convert transmembrane fractalkine into the soluble form, was significantly increased in these cases. Incubation of first-trimester placental explants with TNF-α provoked a significant increase in fractalkine expression and release of the soluble form, whereas IL-6 had no effect. TNF-α-mediated up-regulation of placental fractalkine was reversed in the presence of the aspirin-derivative salicylate, which impaired activation of NF-κB p65 in TNF-α-treated explants. On the basis of data from placental explants, we suggest that increased maternal TNF-α may up-regulate the expression and release of placental fractalkine, which, in turn, may contribute to an exaggerated systemic inflammatory response in PE.

The impact of resilience on psychological outcomes in women after preeclampsia: an observational cohort study

BackgroundPreeclampsia is a frequent obstetric complication which affects the mother`s and the fetus’s health and can be life threatening. It also has an impact on psychological outcomes. There may be protective variables such as resilience shielding against psychosocial distress in women experiencing these pregnancy complications. The aim of this study was to examine differences in resilience in terms of quality of life, depression and post-traumatic stress symptoms in women after preeclampsia.MethodsFour international validated questionnaires were used to measure the psychological outcomes (Medical Outcome Study Short-Form SF12, Edinburgh Postnatal Depression Scale EPDS, Resilience Scale RS13, Impact of Event Scale IES-R). Statistical analyses were performed using independent-samples t-test and chi-square test.Results67 women with previous preeclampsia returned the questionnaires. Women with high resilience showed significantly less depression (p = 0.001) and better mental quality of life (p = 0.002) compared to women with low resilience. No group differences were found on the medical and socio-demographic characteristics.ConclusionsResilience has an important impact on the psychological outcomes in women after preeclampsia. A screening for resilience, depression and quality of life may be appropriate to identify these women.

Endothelin-1 stimulates proliferation of first-trimester trophoblasts via the A- and B-type receptor and invasion via the B-type receptor.

CONTEXT Endothelin-1 (ET-1) stimulates proliferation and invasion of first-trimester human trophoblast cells. OBJECTIVE To test the hypothesis that ET-1 effects are mediated by different receptor subtypes [ET receptor (ETR)-A and ETR-B]. DESIGN The location of ETR in trophoblast cell columns (wk 6-12) was investigated by immunohistochemistry and autoradiography. Trophoblasts were isolated from first-trimester human placentas and proliferative and invasive subpopulations separated using an integrin α6 antibody. Cells were incubated for 24 h with 10 μm ET-1 and different ETR antagonists: PD142893 (unselective), BQ-610 (ETR-A), and RES-701-1 (ETR-B). After ETR down-regulation by antisense oligonucleotides, proliferation (thymidine incorporation, protein synthesis) and invasion (Matrigel invasion) were measured. ETR expression in isolated cells was analyzed by Western blotting and semiquantitative RT-PCR. RESULTS Both ETR are expressed in both subpopulations in the cell column with predominance of ETR-A in the proximal part and proliferative subpopulation, whereas ETR-B is present at similar levels in both subpopulations. These results were confirmed at the mRNA level. ET-1 increased proliferation (maximum 267% of control) and invasion (maximum 288% of control) of first-trimester trophoblasts. The mitogenic ET-1 effect was inhibited (P < 0.05) by 40-80% with each receptor antagonist and by 44 and 40%, respectively, by ETR-A and ETR-B antisense oligonucleotides. The invasion-promoting effect was almost completely blocked in the presence of the ETR-B antagonists. CONCLUSION The effect of ET-1 on cell proliferation in first-trimester trophoblasts is mediated by both ETR, whereas its effect on invasion is mediated predominantly by ETR-B. These effects are in line with the receptor subtype location.

Impact of Mental and Physical Stress on Blood Pressure and Pulse Pressure under Normobaric versus Hypoxic Conditions

Objective Hypobaric hypoxia, physical and psychosocial stress may influence key cardiovascular parameters including blood pressure (BP) and pulse pressure (PP). We investigated the effects of mild hypobaric hypoxia exposure on BP and PP reactivity to mental and physical stress and to passive elevation by cable car. Methods 36 healthy volunteers participated in a defined test procedure consisting of a period of rest 1, mental stress task (KLT-R), period of rest 2, combined mental (KLT-R) and physical task (bicycle ergometry) and a last period of rest both at Graz, Austria (353 m asl) and at the top station Dachstein (2700 m asl). Beat-to-beat heart rate and BP were analysed both during the test procedures at Graz and at Dachstein and during passive 1000 m elevation by cable car (from 1702 m to 2700 m). Results A significant interaction of kind of stress (mental vs. combined mental and physical) and study location (Graz vs. Dachstein) was found in the systolic BP (p = .007) and PP (p = .002) changes indicating that during the combined mental and physical stress task sBP was significantly higher under hypoxic conditions whereas sBP and PP were similar during mental stress both under normobaric normoxia (Graz) and under hypobaric hypoxia (Dachstein). During the passive ascent in cable car less trivialization (psychological coping strategy) was associated with an increase in PP (p = .004). Conclusion Our data show that combined mental and physical stress causes a significant higher raise in sBP and PP under hypoxic conditions whereas isolated mental stress did not affect sBP and PP under hypoxic conditions. PP-reaction to ascent in healthy subjects is not uniform. BP reactions to ascent that represents an accumulation of physical (mild hypobaric hypoxia) and psychological stressors depend on predetermined psychological traits (stress coping strategies). Thus divergent cardiovascular reactions can be explained by applying the multidimensional aspects of the biopsychosocial concept.

Maternal cardiovascular and endothelial function from first trimester to postpartum

Objective To explore noninvasively the complex interactions of the maternal hemodynamic system throughout pregnancy and the resulting after-effect six weeks postpartum. Methods Eighteen women were tested beginning at the 12th week of gestation at six time-points throughout pregnancy and six weeks postpartum. Heart rate, heart rate variability, blood pressure, pulse transit time (PTT), respiration, and baroreceptor sensitivity were analyzed in resting conditions. Additionally, hemoglobin, asymmetric and symmetric dimethylarginine and Endothelin (ET-1) were obtained. Results Heart rate and sympathovagal balance favoring sympathetic drive increased, the vagal tone and the baroreflex sensitivity decreased during pregnancy. Relative sympathetic drive (sympathovagal balance) reached a maximum at 6 weeks postpartum whereas the other variables did not differ compared to first trimester levels. Postpartum diastolic blood pressure was higher compared to first and second trimester. Pulse transit time and endothelial markers showed no difference throughout gestation. However, opposing variables PTT and asymmetric dimethylarginine (ADMA) were both higher six weeks postpartum. Conclusions The sympathetic up regulation throughout pregnancy goes hand in hand with a decreased baroreflex sensitivity. In the postpartum period, the autonomic nervous system, biochemical endothelial reactions and PTT show significant and opposing changes compared to pregnancy findings, indicating the complex aftermath of the increase of blood volume, the changes in perfusion strategies and blood pressure regulation that occur in pregnancy.

Endothelial indoleamine 2,3-dioxygenase-1 regulates the placental vascular tone and is deficient in intrauterine growth restriction and pre-eclampsia

Indoleamine 2,3-dioxygenase-1 (IDO1) mediates the degradation of L-tryptophan (L-Trp) and is constitutively expressed in the chorionic vascular endothelium of the human placenta with highest levels in the microvasculature. Given that endothelial expression of IDO1 has been shown to regulate vascular tone and blood pressure in mice under the condition of systemic inflammation, we asked whether IDO1 is also involved in the regulation of placental blood flow and if yes, whether this function is potentially impaired in intrauterine growth restriction (IUGR) and pre-eclampsia (PE). In the large arteries of the chorionic plate L-Trp induced relaxation only after upregulation of IDO1 using interferon gamma and tumor necrosis factor alpha. However, ex vivo placental perfusion of pre-constricted cotyledonic vasculature with L-Trp decreases the vessel back pressure without prior IDO1 induction. Further to this finding, IDO1 protein expression and activity is reduced in IUGR and PE when compared to gestational age–matched control tissue. These data suggest that L-Trp catabolism plays a role in the regulation of placental vascular tone, a finding which is potentially linked to placental and fetal growth. In this context our data suggest that IDO1 deficiency is related to the pathogenesis of IUGR and PE.

Angiogenic factors in pregnancies of women with antiphospholipid syndrome and systemic lupus erythematosus

OBJECTIVES An imbalance of angiogenic placental factors such as endoglin, soluble fms-like tyrosine kinase 1(sFlt-1) and placental growth factor (PlGF) has been implicated in the pathophysiology of preeclampsia. This study aimed to evaluate serum levels of sFlt-1, PlGF and endoglin in women with primary and secondary antiphospholipid Syndrome (APS) and systemic lupus erythematosus (SLE) longitudinally through pregnancy. MATERIAL AND METHODS Serum levels of sFlt-1, PlGF and endoglin were measured prospectively at 4-week intervals (from gestational weeks 12-36) in 17 women with primary APS (PAPS), 18 women with secondary APS (SAPS), and 23 women with SLE. RESULTS 6/17 (35%) of women with PAPS, 3/18 (17%) of women with SAPS, and 2/23 (9%) of women with SLE developed early-onset preeclampsia. Women who developed preeclampsia had significantly higher mean sFlt-1 and endoglin levels, higher sFlt-1/PlGF ratios, and lower mean PlGF-levels than women who did not. These changes became statistically significant at 12 weeks for sFlt-1, PlGF and endoglin. DISCUSSION Endoglin, sFlt-1 and PlGF are potential early screening parameters for the development of preeclampsia in pregnant women with autoimmune diseases like APS and SLE.

Comparison of two-risk assessment algorithms for preeclampsia in first trimester with consecutive intake of low-dose aspirin in the high-risk group – an observational study

Abstract We analyzed outcome of women screened for preeclampsia with two different multifactorial risk algorithms (Predictor®Software by PerkinElmer, PerkinElmer, Waltham, MA; PERK-group: n = 214 and Viewpoint® by GE Healthcare, Dornstadt, Germany; VIEW-group: n = 209) in first trimester. Women at high risk for developing preeclampsia were advised to take low-dose acetylsalicylic acid (LDA). Screening positive rates for early onset preeclampsia differed significantly between the two groups (7.9% versus 26.3%; p = 0.000). According the clinical use of screening test criteria, LDA was prescribed in 63 (29.4%) women in the PE-group and 55 (26.3%) in the VP-group (p = 0.516). There were no differences in onset of preeclampsia [4 (1.9%) versus 6 (2.9%); p = 0.540]. No early or severe preeclampsia occurred in the whole population.