Expression of voltage-dependent potassium channels in first trimester human placentae

Potassium channel α-subunits encoded by KCNQ1-5 genes form voltage-dependent channels (Kv7), modulated by KCNE1-5 encoded accessory proteins. The aim was to determine KCNQ and KCNE mRNA expression and assess protein expression/localisation of the KCNQ3 and KCNE5 isoforms in first trimester placental tissue. Placentae were obtained from women undergoing elective surgical termination of pregnancy (TOP) at 10 weeks’ (mid TOP) gestations. KCNQ1-5 expression was unchanged during the first trimester. KCNE5 expression increased in mid TOP vs. early TOP samples (P=0.022). This novel study reports mRNA and protein expression of Kv7 channels in first trimester placentae

Is the atherosclerotic phenotype of pre-eclamptic placentas due to altered lipoprotein concentrations and placental lipoprotein receptors?: role of a small-for-gestational-age phenotype

Artherosis of spiral arteries in uteroplacental beds from pre-eclamptic women resemble those of atherosclerosis, characterised by increased plasma lipids and lipoproteins. We hypothesised 1) lipoproteins receptors/transporter in placenta would be up-regulated in pre-eclampsia, associated with increased maternal and fetal lipoprotein concentrations; 2) expression of these would be reduced in pre-eclamptic placentae from women delivering small-for-gestational-age (SGA) infants. Placental biopsies, maternal and umbilical serum samples were taken from 27 normotensive and 24 pre-eclamptic women. Maternal/umbilical cord serum LDL; HDL; total cholesterol and triglycerides were measured. Placental mRNA expression of lipoprotein receptors/transporters were quantified using qRT-PCR. Protein localisation/expression of LRP-1 in the pre-eclamptic with/without SGA was measured by immunohistochemistry. Placental mRNA expression of all genes except PON-1, MTTP and PDIA2 were observed. No differences for any lipoprotein receptors/transporters were found between groups; however, in the pre-eclamptic group placental LRP-1 expression was lower in SGA delivering mothers (n = 7; P=0.036). LRP-1 protein was localised around fetal vessels and Hofbauer cells. This is the first detailed study of maternal/fetal lipoprotein concentrations and placental lipoprotein receptor mRNA expression in normotensive and pre-eclamptic pregnancies. These findings do not support a role of altered lipid metabolism in pre-eclampsia, but may be involved in fetal growth

Born from pre-eclamptic pregnancies predisposes infants to altered cortisol metabolism in the first postnatal year

Pre-eclampsia leads to disturbed fetal organ development, including metabolic syndrome, attributed to altered pituitary-adrenal feedback loop. We measured cortisol metabolites in infants born from pre-eclamptic and normotensive women and hypothesised that glucocorticoid exposure would be exaggerated in the former. Twenty-four hour urine was collected from infants at months 3 and 12. Cortisol metabolites and apparent enzyme activities were analysed by gas chromatography-mass spectrometry. From 3 to 12 months, excretion of THS, THF and pregnandiol had risen in both groups; THF also rose in the pre-eclamptic group. No difference was observed with respect to timing of the visit or to hypertensive status for THE or total F metabolites (P>0.05). All apparent enzymes activities, except 17α-hydroxylase, were lower in infants at 12 compared to 3 months in the normotensive group. In the pre-eclamptic group, only 11β-HSD activities were lower at 12 months.17α-hydroxylase and 11β-HSD activities of tetrahydro metabolites were higher in the pre-eclamptic group at 3 months (P<0.05). 11β-hydroxylase activity increased in the pre-eclamptic group at 12 months. Cortisol excretion, determined by increased 11β-hydroxylase, compensates for high 11β-HSD-dependent cortisol degradation at 3 months and at 12 months counterbalances the reduced cortisol substrate availability in infants born from pre-eclamptic mothers

Placental expression of adenosine A2A receptor and hypoxia inducible factor-1 alpha in early pregnancy, term and pre-eclamptic pregnancies: interactions with placental renin-angiotensin system

Normal placentation occurs under low oxygen tensions yet hypoxia is also implicated in placental pathologies such as pre-eclampsia (PE). Hypoxia-inducible factors (HIFs), adenosine and tissue renin-angiotensin-system (RAS) are known to promote angiogenesis and vascularisation. We hypothesised that placental adenosine A2AR receptor and HIF-1α would change through pregnancy in association with the RAS. Placentae were obtained from women undergoing elective surgical termination of pregnancy (TOP) at ≤10 weeks’ (early TOP) and >10 weeks’ (mid TOP) gestations; at delivery from normotensive (NT) and PE pregnancy. Results were compared to our previously reported data on the angiotensin receptors: AT1R, AT2R and AT4R. Protein expression of both A2AR and HIF-1α was highest in early TOP and positively correlated through pregnancy (P<0.0001): expression was higher in PE than NT at delivery (P<0.0001 for both). The A2AR positively correlated with the AT4R in placentae in early pregnancy (r=0.53; P=0.035), but not in 3rd trimester samples. Our findings suggest a role for adenosine and RAS in promoting placentation and as a potential adaptation to poor placental perfusion in pre-eclampsia

Placental expression of eNOS, iNOS and the major protein components of caveolae in women with pre-eclampsia

Caveolae regulate many cardiovascular functions and thus could be of interest in relation to pre-eclampsia, a pregnancy specific disorder characterised by hypertension and proteinuria. We examined placental mRNA and protein expression/localisation of the caveolae components Caveolin 1-3, Cavin 1-4 as well as eNOS/ iNOS in normotensive control (n=24) and pre-eclamptic pregnancies (n=19). Placental mRNA expression of caveolin-1, cavin 1-3, was lower and eNOS expression was increased in pre-eclampsia (P<0.05 for all). Additionally Caveolin-1 protein expression was also reduced in pre-eclampsia (P=0.007); this could be an adaptive response in pre-eclampsia, possibly to attenuate the oxidative stress/inflammation

The placental renin-angiotensin system and oxidative stress in pre-eclampsia

There is an inverse correlation between human birthweight and umbilical venous angiotensin II (AngII) concentrations. Oxidative stress and increased pro-renin receptor (PRR) both enhance the cleavage of angiotensin I from angiotensinogen (AGT). Pre-eclampsia, a hypertensive disorder of pregnancy, manifests as high blood pressure and proteinuria, and is a state of increased oxidative stress. Objectives, study design and main outcome measures Hypothesis: Pre-eclampsia will be associated with increased placental expression of components of the renin–angiotensin system, which could result in reduced infant birthweight. Biopsies were taken 1 cm from the placental edge from 27 normotensive controls and 23 pre-eclamptic White European women. Immunohistochemistry was performed for AGT, PRR, glutathione peroxidase 3 (GPx3) and the AT1R and AT2R AngII receptors. Protein expression was semi-quantitatively assessed (H-score). Results: AT1R expression was significantly increased in pre-eclamptic placentae, and negatively correlated with birthweight (r = −0.529, P = 0.009). AT1R expression was also negatively correlated with GPx3 expression overall (r = −0.647; P = 0.005). AT2R expression positively correlated with AGT (r = 0.615, P = 0.002) in the pre-eclamptic placentae only. Conclusions: The raised AT1R expression in pre-eclampsia, together with inadequate antioxidant protection, possibly through lower GPx activity, might enhance the vasoconstrictor effect of locally-generated AngII, contributing to the restricted fetal growth characteristic of pre-eclampsia. Conversely, the AT2R:AGT association within the pre-eclamptic placenta may provide a compensatory mechanism

Thyroid hormones and their placental deiodination in normal and pre-eclamptic pregnancy

Pre-eclampsia is associated with lower serum selenium concentrations and glutathione peroxidase expression/activity; total thyroid hormones are also lower. Objectives, study design and main outcome measures: We hypothesised that the placental selenoprotein deiodinase (D3) will be protected in pre-eclampsia due to the hierarchy of selenoprotein biosynthesis in selenium deficiency. Venous blood and tissue from three standardised placental sites were obtained at delivery from 27 normotensive and 23 pre-eclamptic women. mRNA expression and enzyme activity were assessed for both deiodinases (D2 and D3); protein expression/localisation was also measured for D3. FT4, FT3 and TSH concentrations were measured in maternal and umbilical cord blood. Results: No significant differences in D3 mRNA or protein expression between normotensive and pre-eclamptic pregnancies. There was a significant effect of sampling site on placental D3 activity only in pre-eclamptic women (P = 0.034; highest activity nearest the cord). A strong correlation between D3 mRNA expression and enzyme activity existed only in the pre-eclamptic group; further strengthened when controlling for maternal selenium (P < 0.002). No significant differences were observed between groups for any of the maternal thyroid hormones; umbilical TSH concentrations were significantly higher in the pre-eclamptic samples (P < 0.001). Conclusions: D3 mRNA and protein expression appear to be independent of selenium status. Nevertheless, the positive correlation between D3 mRNA expression and activity evident only in pre-eclampsia, suggests that in normotensive controls, where selenium is higher, translation is not affected, but in pre-eclampsia, where selenium is low, enzyme regulation may be altered. The raised umbilical TSH concentrations in pre-eclampsia may be an adaptive fetal response to maximise iodide uptake

Differential expression and distribution of placental glutathione peroxidases 1, 3 and 4 in normal and preeclamptic pregnancy

Preeclampsia is a pregnancy-specific condition affecting 2-7% of women and a leading cause of perinatal and maternal morbidity and mortality; it may also predispose the mother and fetus to increased risks of adult cardiovascular disease. The selenoprotein glutathione peroxidases (GPxs) have critical roles in regulating antioxidant status. Objectives, study design and main outcome measures: Immunohistochemical measurements of GPx 1, GPx3 and GPx4 protein expression were performed on samples taken from three standardised sampling sites between the cord insertion and the periphery of the placenta from 12 normotensive, and 12 preeclamptic women to establish if their expression differed between sampling sites. Total GPx activities were also examined from the three sampling sites of these placentae. Results: There were highly significant reductions in overall immunohistochemical staining of all 3 GPxs in the preeclampsia compared to normotensive placentae (GPx1: P = 0.016; GPx3: P = 0.003; GPx4: P < 0.001). Furthermore, graded differences in expression between the standardised placental sampling sites were also found for GPx3 (higher in the inner region, P = 0.05) and GPx4 (higher in the periphery, P = 0.02) but not GPx1. Placental GPx enzyme activity was also significantly reduced in tissue from preeclamptic women as compared to normotensive women (P = 0.007; the difference was more pronounced nearest the cord insertion). Conclusions: We have shown highly significant reductions in expression of all three major classes of GPx in placentae from women with preeclampsia, and distribution gradients in activity, which may relate to the differential oxygenation of regions of the placenta

Ontogeny and nutritional programming of mitochondrial proteins in the ovine kidney, liver and lung

This study investigated the developmental and nutritional programming of two important mitochondrial proteins, namely voltage dependent anion channel (VDAC) and cytochrome c in the sheep kidney, liver and lung. The effect of maternal nutrient restriction between early to mid gestation (i.e. 28 to 80 days gestation, the period of maximal placental growth) on the abundance of these proteins was also examined in fetal and juvenile offspring. Fetuses were sampled at 80 and 140 days gestation (term ~147 days), and postnatal animals at 1 and 30 days and 6 months of age. The abundance of VDAC peaked at 140 days gestation in the lung, compared with 1 day after birth in the kidney and liver, whereas cytochrome c abundance was greatest at 140 days gestation in the liver, 1 day after birth in the kidney and 6 months of age in lungs. This differential ontogeny in mitochondrial protein abundance between tissues was accompanied with very different tissue specific responses to changes in maternal food intake. In the liver, maternal nutrient restriction only increased mitochondrial protein abundance at 80 days gestation, compared with no effect in the kidney. In contrast, in the lung mitochondrial protein abundance was raised near to term, whereas VDAC abundance was decreased by 6 months of age. These findings demonstrate the tissue specific nature of mitochondrial protein development that reflects differences in functional adaptation after birth. The divergence in mitochondrial response between tissues to maternal nutrient restriction early in pregnancy further reflects these differential ontogeny’s

Maternal selenium, copper and zinc concentrations in pregnancy associated with small-for-gestational-age infants

Pregnancy during adolescence increases the risk of adverse pregnancy outcome, especially risk of small-for gestational-age (SGA) birth, which has been linked to micronutrient deficiencies. Likewise, smoking has been shown to be related with lower micronutrient concentrations. Different ethnicities have not previously been examined. We used a subset from a prospective observational study, the About Teenage Eating (ATE) study consisting of 126 pregnant adolescents (14-18 years old) between 28-32 weeks' gestation. Micronutrient status was assessed by inductively-coupled mass spectrometry. Smoking was assessed by self-report and plasma cotinine, and SGA was defined as infants born < 10th corrected birthweight centile. The main outcome measures were: 1) Maternal plasma selenium, copper and zinc concentrations in adolescent mothers giving birth to SGA versus appropriate-for-gestational-age (AGA) infants. 2) Comparison of micronutrient concentrations between women of different ethnicities and smoking habits. The plasma selenium (mean ± SD [95% CI]) concentration was lower in the SGA (n = 19: 49.4 ± 7.3 [CI: 45.9, 52.9] μg/L) compared to the AGA (n = 107: 65.1 ± 12.5 [CI: 62.7, 67.5] μg/L; P < 0.0001) group. Smoking mothers had a lower selenium concentration compared to non-smokers (P = 0.01) and Afro-Caribbean women had higher selenium concentrations compared to White Europeans (P = 0.02). Neither copper nor zinc concentrations varied between groups, but selenium and copper were moderately correlated (P < 0.05). Selenium is an essential trace element which exerts its biological effects through the expression of a variety of important selenoproteins. Low plasma selenium concentration in adolescent mothers could contribute to the risk of delivering an SGA infant, possibly through lowering the placental antioxidant defence, thus direclty affecting fetal growth. The differences in plasma selenium between different ethnicities may relate to variation in nutritional intake, which requires further investigation