Preeclamptic Pregnancies Research Articles

Levels of blood pressure, cardiovascular biomarkers and their correlations in women with previous pre-eclamptic pregnancy within 7 years postpartum: a cross-sectional study in Thailand

ObjectiveTo assess the levels of blood pressure, cardiovascular biomarkers and their correlations measured within 7 years postpartum in women with previous pre-eclamptic pregnancies compared with women with previous normotensive pregnancies.DesignCross-sectional...

Downregulation of miR-1270 mediates endothelial progenitor cell function in preeclampsia: Role for ATM in the Src/VE-cadherin axis.

Preeclampsia, a pregnancy-related hypertensive disorder, is associated with endothelial dysfunction and increased cardiovascular risk of the offspring in adulthood. In preeclampsia, endothelial colony-forming cells (ECFC) are reduced in number and function. Recently, we have shown that miR-1270, which is involved in cancer in vitro proliferation, migration, and tumor progression, is downregulated in fetal ECFC from preeclamptic pregnancies. We now hypothesize that miR-1270 dysregulation contributes to vascular endothelial dysfunction occurring after preeclampsia via ATM (ataxia telangiectasia mutated) overexpression, the key kinase of DNA damage repair. Here, we show that miR-1270silencing in normal ECFC and downregulation in preeclamptic ECFC are accompanied by an increase in the expression levels of ATM. Furthermore, ATM activation correlates with upregulated tyrosine kinase Src leading to phosphorylation and internalization of VE-cadherin (vascular endothelial-cadherin) which subsequently compromises endothelial barrier permeability and morphodynamic cell parameters. Treatment with specific ATM inhibitors reveals a novel role of ATM upstream of tyrosine kinase Src activation. Subsequently, Src phosphorylation and internalization of VE-cadherin compromise endothelial barrier permeability. Our findings suggest that downregulation of miR-1270 contributes to impaired ECFC function via the associated ATM overexpression, which further identifies ATM as a novel and critical factor for ECFC defects in preeclampsia. Our study provides new insights into the understanding of ECFC impairment associated with cardiovascular risk in preeclamptic offspring and identifies potential novel therapeutic targets.

Level of Uric Acid in Women Suffering from Pre-Eclampsia and its Comparison with Normal Pregnancy

Objective: Current study is conducted to explore the variations in uric acid level in pre-eclamptic and normal healthy pregnancy in its third trimester in pregnant females. Methods: This descriptive cross sectional study was conducted to measure the serum uric acid level in mg/dl by kit method. The cutoff value was kept at 5mg/dl. The 10 ml of midstream urine was collected for estimation of urinary protein by dipstick method and graded from +1 to +3. For comparison between two groups in terms of levels of uric acid, independent sample t-test was used. Pearson Chi Square test was used to compare qualitative variables. Results: Raised levels of uric acid were obtained in 81.6% preeclampsia samples, and 13.1% found among normal samples, p<0.01 showed that level of serum uric acid has a significant relationship with preeclampsia. Independent sample t-test showed a significant mean difference for SBP, DBP, and SUA between two groups, (p<0.01) Conclusion: Significant high level of serum uric acid level was found in pre-eclamptic females than normotensive women. The findings suggest that measurement of serum uric acid may be a suitable marker in diagnosis of pre-eclampsia. Keywords: Pregnancy, Pre-eclampsia, Serum Uric Acid, Hypertension

Fetal out comes in Pre-Eclampsia with raised Maternal Serum Uric Acid

Aim: To compare adverse fetal outcome of hyperuricemic pre-eclamptic pregnancy with normouricemic pre-eclamptic pregnancy. Study design: A Cohort Study Methodology: In this study patients with serum uric acid level(SUA) >5.5mg/dl were included in group A and patients with SUA level <5.5mg/dl were included in group B. Patients with medical disorders like renal disease, hypertension, diabetes and currently using drugs affecting uric acid levels like thiazide diuretics were excluded. Both groups were followed until delivery. Intrauterine growth restriction, low birth weight was recorded. Results: A total of sixty patients were studied with age range from 18 to less than 40 years. The mean age in group A was 33.566± 4.19 years while 34.100± 3.46 years in group B. Mean Gestational age was 33.500±4.22 weeks in group A and 34.200±4.71 weeks in group B, while mean serum uric acid level was 7.416±1.04 in group A and 4.202±0.61 in group B. Intrauterine growth restriction was seen 93.3% in group A as compare to 60% in group B (P=0.002)(RRR=55.5%) while Low birth weight was 70% in group A and 10% in group B (P=0.000). Conclusion: The pregnancies with pre-eclampsia and raised serum uric acid levels result in adverse fetal outcome. Significant increased number of IUGR and LBW fetuses were observed in babies born to pre-eclamptic mothers with raised serum uric acid levels in comparison with babies born to normo-uricemic pre eclamptic mothers. Keywords: Pre-eclampsia, serum uric acid, fetal outcome

Sympathetic Responses to Isometric Handgrip Exercise in Women following Preeclamptic Pregnancies

Women who have had preeclamptic (PE) pregnancies are at increased risk for developing cardiovascular diseases later in life. One potential mechanism that may mediate this increased risk is sympathetic dysregulation. Indeed, there is evidence for elevated muscle sympathetic nerve activity (MSNA) both during and following PE pregnancies. Moreover, previously PE (PPE) women may demonstrate impaired MSNA responses during stress, although this has only been examined to a limited extent. Therefore, we tested the hypothesis that MSNA responses to isometric hand grip exercise (HG) would be greater in PPE women (n=6, age 31±6 years, BMI 29±5 kg/m2, 17±4 months postpartum) compared with women who had a healthy pregnancy (HP; n=8, age 29±2, BMI 25±4 kg/m2, 14±4 months postpartum). MSNA (peroneal nerve microneurography), mean arterial pressure (MAP; finger photoplethysmography), and total peripheral resistance (TPR; MAP/cardiac output), were assessed at baseline, during a 2‐min HG protocol, and during 2‐min post‐exercise circulatory occlusion (PECO). As previously reported, baseline MSNA was higher in PPE than HP (22±7 vs 13±5 bursts/min, P=0.01). Baseline MAP was not different between PPE and HP (94±11 vs 89±9 mmHg, P=0.23), nor was TPR (13±3 vs 13±2 mmHg/L/min, P=0.63). During HG, MSNA was greater in PPE than HP (24±8 vs 16±6 bursts/min, P=0.03), whereas MAP was not different between PPE and HP (95±12 vs 95±11 mmHg, P=0.99), nor was TPR (13±3 vs 14±2 mmHg/L/min, P=0.39). During PECO, no differences were observed between PPE and HP women in MSNA (26±8 vs 18±6 bursts/min, P=0.08), MAP (93±12 vs 96±12 mmHg, P=0.70), or TPR (12±3 vs 15±2 mmHg/L/min, P=0.18). These findings indicate that PPE women demonstrate exaggerated MSNA during isometric HG exercise relative to HP women, although the role of the metaboreflex in mediating this effect, as assessed using PECO, remains unclear. Importantly, these data also demonstrate that young PPE women were able to buffer the deleterious cardiovascular outcomes of elevated MSNA such that MAP and TPR outcomes were similar to age‐matched HP women during all conditions.

Elevated Urinary Arginine Vasopressin Concentrations during Preeclamptic Pregnancies do not Persist Postpartum

BackgroundPreeclampsia (PreE) is a common hypertensive disorder during the second and third trimesters of pregnancy. It is estimated to affect 5‐7% of all U.S. pregnancies; about 400,000 pregnancies per year. PreE leads to increased risks of fetal abnormalities, pregnancy complications, chronic hypertension, and cardiovascular disease. Arginine vasopressin (AVP) plays an important role in controlling osmotic balance, regulating blood pressure, maintaining sodium homeostasis, and functioning of the kidney. AVP is secreted by the hypothalamus as a proprotein with copeptin. Because copeptin and vasopressin are secreted in a 1:1 molar ratio, copeptin measurements can be used a surrogate measure of vasopressin. Our lab has previously demonstrated that vasopressin, as measured by copeptin, is elevated in plasma and urine throughout preeclamptic pregnancies; even before PreE can be clinically diagnosed. However, it is unknown whether urine vasopressin is elevated chronically postpartum. Our objective was to determine whether there is a difference in copeptin concentration between women with and without a history of preeclampsia at 1‐4 years postpartum. We hypothesized that AVP concentrations of subjects who had received a PreE diagnosis would continue to be elevated postpartum.MethodsInclusion criteria for this study (IRB# 201808705) included being 1‐4 years postpartum, not currently pregnant, non‐prisoner, and able to provide informed consent. Women without (N=26; Age 34 +/‐ 3.4 yrs, BMI 25.99 +/‐ 6.34 kg/m2) and with a history (N=25; age 33 +/‐ 4.5 yrs, BMI 30.32 +/‐ 9.12 kg/m2) of preeclampsia in their most recent pregnancy were enrolled. Women fasted, did not smoke, and did not have caffeine for 4 hours prior to their study visit, nor did they have alcohol or exercise for the prior 24 hours. Urine samples were assayed for copeptin concentrations via an automated immunoassay (Brahms KRYPTOR), creatinine concentrations via a QuantiChrom assay, total protein concentrations via a bicinchoninic acid (BCA) protein assay, osmolality by freezing point depression, and specific gravity using a hydrometer.ResultsThere were no differences between the cohorts in race or ethnicity. There was no statistically significant difference in urinary copeptin, as a marker of AVP, in the postpartum period between women with vs. without a history of preeclampsia (4.5 vs. 3.2 mg/dL, P=0.4). No significant differences in copeptin were detected in women without a current hypertension diagnosis (5.49 mg/dL, N=43) and those being treated for hypertension (4.79 mg/dL, N=7, P=0.35).ConclusionsThis study suggests that copeptin, a surrogate measure for AVP, is not chronically elevated in urine after a preeclamptic pregnancy.

Umbilical cord plasma from preeclamptic pregnancies reduce brain endothelial cell migration

Umbilical cord plasma from preeclamptic pregnancies reduce brain endothelial cell migration

Long-term effects of preeclampsia on maternal cardiovascular health and postpartum utilization of primary care: an observational claims data study

PurposePreeclampsia occurs in up to 15% of pregnancies and constitutes a major risk factor for cardiovascular disease. This observational cohort study aimed to examine the association between preeclamptic pregnancies and cardiovascular outcomes as well as primary and specialized care utilization after delivery.MethodsUsing statutory claims data we identified women with singleton live births between 2010 and 2017. Main outcomes included the occurrence of either hypertension or cardiovascular disease after one or more preeclamptic pregnancies, number of contacts to a general practitioner or cardiologist after delivery and prescribed antihypertensive medication. Data were analyzed using Cox proportional hazard regression models adjusted for maternal age, diabetes, dyslipidemia, and obesity.ResultsThe study cohort consisted of 181,574 women with 240,698 births. Women who experienced preeclampsia once had an increased risk for cardiovascular (hazard ratio, HR = 1.29) or hypertensive (HR = 4.13) events. In women affected by recurrent preeclampsia, risks were even higher to develop cardiovascular disease (HR = 1.53) or hypertension (HR = 6.01). In the following years after delivery, general practitioners were seen frequently, whereas cardiologists were consulted rarely (0.3 and 2.4%).ConclusionWomen affected by preeclampsia experience an increased risk of developing chronic hypertension and cardiovascular disease, especially those with recurrent preeclampsia. Future medical guidelines should take this potential risk into account.

MiR-486-5p inhibits invasion and migration of HTR8/SVneo trophoblast cells by down-regulating ARHGAP5

IntroductionAppropriate implantation of trophoblast cells is necessary for successful pregnancy outcome. This process requires proper migration and invasion of trophoblast cells into the maternal endometrium and the myometrium. Dysregulation of circulating microRNAs in preeclampsia has been reported in several studies. Furthermore, miR-486-5p was reportedly increased within exosomes derived from maternal circulation in preeclamptic pregnancy. However, the roles of elevated miR-486-5p in preeclampsia has not yet been clarified. MethodsHTR8/SVneo trophoblast cells were transfected with miR-486-5p, and the ARHGAP5 expression was examined by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blotting. A reporter assay using a luciferase construct containing the ARHGAP5 3′-untranslated region (3′UTR) was performed to determine whether or not ARHGAP5 is a direct target of miR-486-5p. Changes in migration and invasion abilities were examined by a wound healing assay and invasion assay, respectively. ResultsThe ARHGAP5 expression was significantly decreased in miR-486-5p-transfected cells according to RT-qPCR and Western blotting. A dual luciferase reporter gene assay showed that miR-486-5p acts directly on the 3′UTR of ARHGAP5 mRNA. The migration and invasion abilities were suppressed in miR-486-5p-transfected cells. Downregulation of ARHGAP5 by small interfering RNA transfection inhibited trophoblast cell migration and invasion, resembling that of miR-486-5p transfection. DiscussionThe migration and invasion abilities of HTR8/SVneo cells were suppressed by miR-486-5p at least partly through inhibiting the ARHGAP5 expression. These data suggest that miR-486-5p is involved in the pathogenesis of preeclampsia and that miR-486-5p is a viable potential biomarker for predicting the onset risk of preeclampsia.

Impairment of mitochondrial respiration in platelets and placentas: a pilot study in preeclamptic pregnancies

Preeclampsia (PE) is a major complication of pregnancy with partially elucidated pathophysiology. Placental mitochondrial dysfunction has been increasingly studied as major pathomechanism in both early- and late-onset PE. Impairment of mitochondrial respiration in platelets has recently emerged as a peripheral biomarker that may mirror organ mitochondrial dysfunction in several acute and chronic pathologies. The present study was purported to assess mitochondrial respiratory dys/function in both platelets and placental mitochondria in PE pregnancies. To this aim, a high-resolution respirometry SUIT (Substrate-Uncoupler-Inhibitor-Titration) protocol was adapted to assess complex I (glutamate + malate)- and complex II (succinate)-supported respiration. A decrease in all respiratory parameters (basal, coupled, and maximal uncoupled respiration) in peripheral platelets was found in preeclamptic as compared to healthy pregnancies. At variance, placental mitochondria showed a dichotomous behavior in preeclampsia in relation to the fetal birth weight. PE pregnancies with fetal growth restriction were associated with decreased in coupled respiration (oxidative phosphorylation/OXPHOS capacity) and maximal uncoupled respiration (electron transfer/ET capacity). At variance, these respiratory parameters were increased for both complex I- and II-supported respiration in PE pregnancies with normal weight fetuses. Large randomized controlled clinical studies are needed in order to advance our understanding of mitochondrial adaptive vs. pathological changes in preeclampsia.

Evaluation of maternal ophthalmic artery Doppler indices and its correlation with fundoscopic changes in normotensive and pre-eclamptic pregnancies: A comparative study

Background: Preeclampsia is a multisystem disease characterized by the development of hypertension after 20 weeks of gestation in a previously normotensive woman with the presence of proteinuria, severity leading to target organ injury, including liver, kidney, heart, lungs, brain and pancreas. We evaluated the ophthalmic artery Doppler indices (PSV, EDV, PI, RI) in normotensive and in pre-eclampic pregnancies and correlated the Doppler indices changes with fundoscopic findings. Materials and methods: Orbital Ultrasonography was performed on the pregnant women who developed high blood pressure after 20 weeks of gestation and on the normal pregnant women as control and the Doppler indices of ophthalmic artery were determined. Fundoscopic examination of the patients was done with direct ophthalmoscope. Hypertensive Retinal changes observed in both eyes were taken as positive findings. Results: The study showed that PSV, RI and PI and S/D ratio were reduced in pre-eclampic patients when compared with healthy normotensive pregnant women while EDV was increased in pre-eclampic patients when compared with healthy normotensive pregnant women. Statistically significant relationship among Doppler parameters namely PSV, EDV, PI, RI, S/D values between normotensive and pre-eclampic patients was noted. Fundoscopic changes were noted among sever pre-eclampsia patients. Conclusions: Ophthalmic artery Doppler Ultrasonography can detect pre-eclampsia in early stages when compared to fundoscopy and is a cheap, noninvasive, readily available, safe, and reliable tool for evaluation of the central hemodynamic changes in normal pregnancy, and even more so in PE.

Circulating Levels of Anti-C1q and Anti-Factor H Autoantibodies and Their Targets in Normal Pregnancy and Preeclampsia.

Preeclampsia (PE) generally manifests in the second half of pregnancy with hypertension and proteinuria. The understanding of the origin and mechanism behind PE is incomplete, although there is clearly an immune component to this disorder. The placenta constitutes a complicated immune interface between fetal and maternal cells, where regulation and tolerance are key. Stress factors from placental dysfunction in PE are released to the maternal circulation evoking the maternal response. Several complement factors play a role within this intricate landscape, including C1q in vascular remodeling and Factor H (FH) as the key regulator of alternative pathway complement activation. We hypothesize that decreased levels of C1q or FH, or disturbance of their function by autoantibodies, may be associated with PE. Autoantibodies against C1q and FH and the concentrations of C1q and FH were measured by ELISA in maternal sera from women with preeclamptic and normal pregnancies. Samples originated from cohorts collected in the Netherlands (n=63 PE; n=174 control pregnancies, n=51 nonpregnant), Finland (n=181 PE; n=63 control pregnancies) and Norway (n=59 PE; n=27 control pregnancies). Serum C1q and FH concentrations were higher in control pregnancy than in nonpregnant women. No significant differences were observed for serum C1q between preeclamptic and control pregnancy in any of the three cohorts. Serum levels of FH were lower in preeclamptic pregnancies compared to control pregnancies in two of the cohorts, this effect was driven by the early onset PE cases. Neither anti-C1q autoantibodies nor anti-FH autoantibodies levels differed between women with PE and normal pregnancies. In conclusion, levels of anti-C1q and anti-FH autoantibodies are not increased in PE. C1q and FH are increased in pregnancy, but importantly, a decrease in FH concentration is associated with PE.

Vitamin D stimulates placental L-type amino acid transporter 1 (LAT1) in preeclampsia

Vitamin D insufficiency/deficiency has been linked to an increased risk of preeclampsia. Impaired placental amino acid transport is suggested to contribute to abnormal fetal intrauterine growth in pregnancies complicated by preeclampsia. However, if vitamin D-regulated amino acid transporter is involved in the pathophysiologic mechanism of preeclampsia has not been clarified yet. The aberrant expression of key isoform of L-type amino acid transporter LAT1 was determined by western blot and immunohistochemistry in the placenta from normotensive and preeclamptic pregnancies. The role for vitamin D on placental LAT1 expression was investigated through the exposure of HTR-8/SVneo human trophoblast cells to the biologically active 1,25(OH)2D3 and the oxidative stress-inducer cobalt chloride (CoCl2). Our results showed that placental LAT1 expression was reduced in women with preeclampsia compared to normotensive pregnancies, which was associated with decreased expression of vitamin D receptor (VDR). 1,25(OH)2D3 significantly upregulated LAT1 expression in placental trophoblasts, and also prevented the decrease of mTOR activity under CoCl2-induced oxidative stress. siRNA targeting VDR significantly attenuated 1,25(OH)2D3-stimulated LAT1 expression and mTOR signaling activity. Moreover, treatment of rapamycin specifically inhibited the activity of mTOR signaling and resulted in decrease of LAT1 expression. In conclusion, LAT1 expression was downregulated in the placenta from women with preeclampsia. 1,25(OH)2D3/VDR could stimulate LAT1 expression, which was likely mediated by mTOR signaling in placental trophoblasts. Regulation on placental amino acid transport may be one of the mechanisms by which vitamin D affects fetal growth in preeclampsia.

Assessment of the Systemic Oxidative Stress in Preeclampsia

Abstract Preeclampsia (PE) is a major complication of pregnancy with both mother and fetal adverse outcomes. Pregnancy is a state of increased oxidative stress that has been reported to be exacerbated when complicated with preeclampsia. However, conflicting data are available in literature regarding the systemic oxidative stress in PE pregnancies. The present pilot study was purported to assess systemic oxidative stress in preeclamptic vs healthy pregnancies. To this aim plasma derived compounds of reactive oxygen metabolites (d-ROMs) and the biological antioxidant potential (BAP) were determined in mild and severe preeclamptic pregnancies using the Diacron equipment. Both healthy and preeclamptic pregnancies showed high levels of systemic oxidative stress. Paradoxically, significantly higher values of d-ROMs were found in healthy pregnancies as compared to the PE ones. At variance, in preeclamptic pregnancies, a major increase in the plasma antioxidant capacity occurred. In this pilot study, we report an increase in the systemic antioxidant capacity in preeclamptic pregnancies.

Acute systemic inhibition of inflammation augments endothelium-dependent dilation in women with a history of preeclamptic pregnancy.

Women who have had preeclampsia demonstrate microvascular endothelial-dysfunction, mediated in part by reduced nitric oxide (NO)-dependent dilation. Preeclamptic pregnancies are associated with elevated inflammation, and inhibition of inflammation attenuates endothelial damage in animal models of preeclampsia. However, it is unclear if inhibition of vascular inflammation improves endothelial function in women after a preeclamptic pregnancy. Using the cutaneous microcirculation as a model, we hypothesized that acute systemic inhibition of vascular inflammation (oral salsalate; 1500mg/twice daily, 4days) would improve endothelium- and NO-dependent vasodilation in women with a history of preeclampsia (PE) but not in women with a history of uncomplicated pregnancy (HC). Twelve HC (30±1yrs, 10±2months postpartum) and 10 PE (30±2yrs, 8±2months postpartum) participated in a double-blind placebo-controlled study. Following each treatment, 2 intradermal microdialysis fibers were placed in the skin of the ventral forearm for graded infusion of acetylcholine (Ach, 10-7-102mM) or Ach+15mM L-NAME (NO synthase antagonist). Red blood cell flux was measured over each site by laser-Doppler flowmetry (LDF). Cutaneous vascular conductance was calculated (CVC=LDF/mean arterial pressure) and normalized to maximum (%CVCmax; 28mM SNP+local heat 43°C). ACh-induced (77±3 vs. 92±3%CVCmax; p=0.01) and NO-dependent (20±6 vs. 33±4%; p=0.02) vasodilation were attenuated in PE compared to HC. Salsalate augmented ACh-induced (95±2%CVCmax; p=0.002) and NO-dependent (39±3%; p=0.009) dilation in PE compared to placebo but had no effect in HC (all p>0.05). Salsalate treatment augmented endothelium-dependent vasodilation via NO-mediated pathways in women who have had preeclampsia, suggesting that inflammatory signaling mediates persistent endothelial dysfunction following preeclampsia.

Expression of ABC transporters during syncytialization in preeclampsia.

Preeclampsia complicates 2-8% of pregnancies and is associated with prematurity and intrauterine growth restriction. Cholesterol and sterol transport is a key function of the placenta and it is elicited through ATP binding cassette (ABC) transporters. ABCA1 expression changes during trophoblast cell fusion, a process required to form the placental syncytium that enables maternal-fetal nutrient transfer. ABCA1 expression is dysregulated in preeclamptic placentas. But whether ABC transporters expression during trophoblast fusion is disrupted in preeclampsia remains unknown. We investigated if cholesterol and sterol ABC transporters are altered in term and preterm preeclampsia placentas and during human cytotrophoblast syncytialization. Human placental biopsies were collected from healthy term (≥37weeks; n=11) and term preeclamptic (≥36 6/7 weeks; n=8) and pre-term preeclamptic (28-35weeks; n=8) pregnancies. Both, protein and mRNA expression for ABCA1, ABCG1, ABCG5, and ABCG8 were evaluated. Primary cytotrophoblasts isolated from a subset of placentas were induced to syncytialize for 96h and ABCA1, ABCG1 and ABCG8 mRNA expression evaluated at 0h and 96h. Protein and gene expression of ABC transporters were not altered in preeclamptic placentas. In the healthy Term group, ABCA1 expression was similar before and after syncytialization. After 96h of syncytialization, mRNA expression of ABCA1 and ABCG1 increased significantly, while ABCG8 decreased significantly in term-preeclampsia, but not pre-term preeclampsia. While placental expression of ABCA1 and ABCG1 remained unaltered in term preeclampsia, the disruption in their dynamic expression pattern during cytotrophoblast syncytialization suggests that cholesterol transport may contribute to the pathophysiologic role of the placenta in preeclampsia.

G-Protein Coupled Receptor Dysregulation May Play Roles in Severe Preeclampsia—A Weighted Gene Correlation Network Analysis of Placental Gene Expression Profile

Preeclampsia is one of the major hypertensive diseases of pregnancy. Genetic factors contribute to abnormal placentation. The inadequate transformation of cytotrophoblasts causes failure of maternal spiral arteries’ remodeling and results in narrow, atherotic-prone vessels, leading to relative placental ischemia. This study aims to explore the possibility of identifying dysregulated gene networks that may offer a potential target in the possible prevention of preeclampsia. We performed a weighted gene correlated network analysis (WGCNA) on a subset of gene expression profiles of placental tissues from severe preeclamptic pregnancies. We identified a gene module (number of genes = 402, GS = 0.35, p = 0.02) enriched for several G-protein-coupled receptor (GPCR)-related genes with significant protein–protein molecular interaction (number of genes = 38, FDR = 0.0007) that may play key roles in preeclampsia. Some genes are noted to play key roles in preeclampsia, including LPAR4/5, CRLR, NPY, TACR1/2, and SFRP4/5, whose functions generally relate to angiogenesis and vasodilation or vasoconstriction. Other upregulated genes, including olfactory and orexigenic genes, serve limited functions in the disease pathogenesis. Altogether, this study shows the utility of WGCNA in exploring possible new gene targets, and additionally reinforces the feasibility of targeting GPCRs that may offer intervention against development and disease progression among severe preeclampsia patients.

Malondialdehyde and Neutrophil Gelatinase-Associated Lipocalin as Markers of Oxidative Stress in Small for Gestational Age Newborns from Hypertensive and Preeclamptic Pregnancies.

Introduction It is speculated that preeclampsia and hypertension during pregnancy are associated with an imbalance of the placental antioxidant defence, which results in the overproduction of reactive oxygen species and fetal growth restriction. Many research implied that oxidant stress in utero may be an important determinant of mortality and morbidity in neonates. Moreover, the authors demonstrated the reduced number of nephrons and a higher prevalence of renal injury in neonates with growth restriction, including small for gestational age (SGA) neonates. Alas, it remains unclear whether basal antioxidant status is altered in the kidneys of SGA newborns. Materials and Methods In this study, we assessed neutrophil gelatinase-associated lipocalin (NGAL) and malondialdehyde (MDA) levels in samples collected from umbilical blood and 12 hours after delivery in neonates born by mothers suffering from preeclampsia or hypertension during pregnancy and those from physiological pregnancies. Additionally, the authors evaluated levels of the aforementioned biomarkers regarding the occurrence of growth restriction in newborns. For this study, we enrolled 27 newborns, which fulfilled inclusion criteria for SGA diagnosis (SGA group), while 21 were appropriate for gestational age neonates, as the AGA group. Results In the presented study, we have found significant differences in umbilical cord MDA and NGAL concentration between the SGA and AGA groups. Such dependencies were not found in blood samples from neonates collected in the first 12 hours of life for MDA and NGAL concentrations. Additionally, we have observed differences in umbilical MDA and NGAL levels between newborns of preeclamptic or hypertensive mothers compared to healthy ones. A significant correlation between the occurrence of hypertension during pregnancy and umbilical MDA and NGAL concentrations was also found. Conclusions Small for gestational age newborns or those born by preeclamptic and hypertensive mothers had significantly higher MDA and NGAL levels as compared to healthy ones. Further investigation is needed to understand the pathophysiologic influence of hypertension in pregnancy and oxidative stress injury in newborns with growth restriction.

Evaluation of the PLAC8 Gene in Mexican Women With and Without Preeclampsia and Obesity.

Preeclampsia (PE) is a leading cause of maternal-fetal mortality worldwide, and obesity is an important risk factor. Genes associated with pathophysiological events common to preeclampsia and obesity, such as PLAC8, remain to be studied; therefore, the aim of the present study was to evaluate this gene in the placentas of women affected with preeclampsia and healthy pregnant women. This case-controlled study included 71 healthy and 64 preeclampsia pregnancies. Gene expression was evaluated in primary human cytotrophoblasts (PHCT) from six normal and six preeclampsia pregnancies, and protein expression was verified in placentas from five healthy and six preeclampsia pregnancies. The whole coding and 5′ regions of the PLAC8 gene were sequenced from healthy (n = 10) and preeclamptic (n = 10) pregnancies. The presence of the observed nucleotide variations was analyzed by RT-PCR in the total population. Statistical analyses were performed accordingly. Obesity was associated with severe preeclampsia (SPE) (OR = 3.34; CI 95% 1.3–8.2, p < 0.01). Significantly higher mRNA and protein expression was observed in preeclamptic vs. healthy placentas (p < 0.05). After sequencing, a single nucleotide variation was identified in 10 cases and one control (p < 0.01), which was then evaluated in the total population showing no association with preeclampsia. This preliminary study confirms the association of SPE with obesity and suggests higher expression of PLAC8 mRNA and protein in placentas from preeclampsia. No differences in nucleotide variations between cases and controls of the whole population were observed. Further research is required to evaluate the implications of higher gene/protein expression in preeclampsia and the causes of such variation.

Procyanidin B2 ameliorates endothelial dysfunction and impaired angiogenesis via the Nrf2/PPARγ/sFlt-1 axis in preeclampsia

Preeclampsia is a severe complication of pregnancy characterised by variable degrees of placental malperfusion. A growing body of evidence indicates that soluble endoglin and soluble fms-like tyrosine kinase-1 (sFlt-1) play important pathophysiological roles in preeclampsia, causing endothelial dysfunction, hypertension, and multiorgan injury. A drug that is safe in pregnancy and inhibits placental sFlt-1 and soluble endoglin secretion would be an attractive treatment strategy for preeclampsia. Procyanidin B2, a bioactive food compound, has been reported to exert multiple beneficial functions. Placental explant cultures in vitro are useful for studying tissue functions including release of secretory components, pharmacology, toxicology, and disease processes. The reduced uterine perfusion pressure (RUPP) rat model has been widely used as a model of preeclampsia. We aimed to investigate the effect of procyanidin B2 on preeclampsia via using placental explant cultures and RUPP rat model. In this study, we demonstrated that procyanidin B2 reduced soluble endoglin and sFlt-1 secretion from human umbilical vein endothelial cells (HUVECs), primary trophoblasts, and placental explants from preeclamptic pregnancies. Moreover, procyanidin B2 alleviated endothelial dysfunction and impaired angiogenesis induced by sFlt-1, including increasing the migration, invasion and angiogenesis of endothelial cells and decreasing the expression of vascular cell adhesion molecule-1 (VCAM-1) and leukocyte adhesion on HUVECs. In addition, procyanidin B2 promoted nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear accumulation and induced peroxisome proliferator-activated receptor γ (PPARγ) expression in primary placental tissues and endothelial cells. Importantly, Nrf2 specifically binds to the PPARγ promoter region (-1227/-1217) and enhances its transcriptional activity. Procyanidin B2 inhibits sFlt-1 secretion via the Nrf2/PPARγ axis. In the RUPP rat model of preeclampsia, procyanidin B2 attenuated RUPP-induced maternal angiogenic imbalance, hypertension and improved placental and foetal weight. Taken together, our results demonstrate that procyanidin B2 inhibits sFlt-1 secretion and ameliorates endothelial dysfunction and impaired angiogenesis via the Nrf2/PPARγ axis in preeclampsia. Procyanidin B2 may be a novel therapeutic agent for treatment of preeclampsia.