Function In Preeclampsia Research Articles

Assessment of High Serum Cystatin C as an Early Marker of Renal Impairment in Pre Eclampsia

Introduction: Preeclampsia is the most common medical complication during pregnancy and one of the leading causes of maternal and perinatal morbidity and mortality in Bangladesh. Kidney has role in both adaptive physiology of normal pregnancy and in pathophysiology of preeclampsia. Among the new biomarkers, serum Cystatin C can reliably reflect the GFR in both healthy and hypertensive pregnant women. It is important to evaluate the diagnostic efficiency of Cystatin C as a marker of renal function in preeclampsia. Aim: To assess high serum Cystatin C level as an early marker of renal impairment in pre-eclamptic patients. Materials and Methods: From March, 2021 to February, 2022 (A total of 12 months) a cohort study was conducted among 66 pregnant women, aged 18 to 40 years with pre-eclampsia and normal serum creatinine (0.5-0.8mg/dl) at their 20-28 weeks of gestation attending the antenatal clinic and admitted in the Department of Feto maternal Medicine, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, selected by non random purposive and convenient sampling. Results: Out of 66 respondents, final analysis was done with 62 patients. Among 62 study samples, 76% patients had “High Cystatin C” level that was greater than 0.84 and renal impairment developed in 15% pregnant women. Majority of the participants were in 25-30 age groups (46.8%). The mean serum creatinine level of the pregnant women increased throughout follow up and it was statistically significant (p<0.05) in both cases. No significant difference was found between serum Cystatin C in renal impaired and normal renal function pre eclampsia patients at a cut off value of 0.84. ROC analysis of serum Cystatin C level for detection of renal impairment among Pre eclamptic patients found a cut-off value of ≥1.49 showed the highest Youden index of 0.721. The sensitivity, specificity, PPV, NPV and accuracy of serum Cystatin C were 77.78%, 94.34%, 70.00%, 96.15% and 91.94%. Conclusion: Higher Cystatin C level in pre-eclampsia reflected renal impairment at an early stage even before conventional marker like serum creatinine raise. The diagnostic efficiency of Cystatin C as a marker of renal function in pre eclampsia can be used to reduce maternal morbidity and mortality of Bangladesh. Medicine Today 2023 Vol.36 (1): 12-16

High level 27-HC impairs trophoblast cell invasion and migration via LXR in pre-eclampsia

IntroductionTo explore the potential impact of 27-hydroxycholesterol (27-HC) on trophoblast cell function in pre-eclampsia. ResultsThe levels of 27-HC and the expression of CYP27A1 are upregulated in clinical samples of PE. Furthermore, high concentrations of 27-HC can inhibit the invasion and migration ability of trophoblast cells in vitro, and this inhibitory effect is weakened after LXR silencing. In HTR8/SVneo cells treated with 27-HC, the expression of ABCA1/ABCG1 are increased. Finally, we established a mouse model of PE using l-NAME (N-Nitro-l-Arginine Methyl Ester). We found an increase in the levels of 27-HC in the peripheral blood serum of the PE mouse model, and an upregulation of CYP27A1 and LXR expressions in the placenta of the PE mouse model. Conclusion27-HC inhibits the invasion and migration ability of trophoblast cells by activating the LXR signaling pathway, which is involved in the pathogenesis of Pre-eclampsia(PE).

Tandem mass tag-based proteomics analysis reveals the mechanism underlying the interleukin-6-mediated regulation of trophoblast function in preeclampsia

Objective We investigated the mechanism whereby interleukin-6 (IL-6), an important inflammatory marker, influences trophoblast function during preeclampsia. Methods Quantitative PCR and enzyme-linked immunosorbent assay were used to determine the IL-6 mRNA and protein levels, respectively. CCK8 and transwell assays were used to detect how IL-6 affects the proliferation and invasion abilities of HTR-8/SVneo cells respectively; the tube-forming assay was conducted to explore how IL-6 affects the angiogenesis ability of human umbilical vein endothelial cells (HUVECs) after their co-culture with HTR-8/SVneo cells. Using tandem mass tag-based proteomics analysis, we screened for different proteins before and after IL-6 stimulation; Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed to investigate the functions and signal pathways associated with these proteins. Results The IL-6 levels were higher in the placenta of preeclampsia group than in the normal group. IL-6 suppressed the proliferation and invasion of HTR-8/SVneo cells, but promoted the angiogenesis of HUVECs. Seventy differentially expressed IL-6 downstream proteins were identified; these were enriched with various biological processes, molecular functions, cellular components, and biological pathways. Conclusions: IL-6 regulates trophoblast function by interacting with multiple proteins and pathways. Proteomics-based screening serves as a macroscopic approach to clarify the molecular mechanisms associated with preeclampsia.

Study of heart function in PRE-Eclampsia during and after PreGnancy (SHePREG): The pilot cohort

BackgroundPre-eclampsia with severe features (severe PreE) is associated with heart dysfunction, yet the impact beyond pregnancy, including its association with cardiomyopathic genetic polymorphisms, remains poorly understood. ObjectiveWe aimed to characterize the temporal impact of severe PreE on heart function through the 4th trimester in women with and without deleterious cardiomyopathic genetic variants. MethodsPregnant women were enrolled to undergo transthoracic echocardiography (TTE) in late pregnancy and 3 months postpartum. In women with severe PreE a targeted approach to identify pathogenic cardiomyopathic genetic polymorphisms was undertaken, and heart function was compared in carriers and non-carriers. ResultsPregnant women (32 ± 4 years old, severe PreE = 14, control = 8) were enrolled between 2019 - 2021. Women with severe PreE displayed attenuated myocardial relaxation (mitral e’ = 11.0 ± 2.2 vs. 13.2 ± 2.3 cm/sec, p < 0.05) in late pregnancy, and on in-silico analysis, deleterious cardiomyopathic variants were found in 58%. At 103 ± 33 days postpartum, control women showed stability in myocardial relaxation (Mitral e’ Entry: 13.2 ± 2.3 vs. Postpartum: 13.9 ± 1.7cm/sec, p = 0.464), and genetic negative severe PreE women (G-) demonstrated recovery of diastolic function to control level (Mitral e’ Entry: 11.0 ± 3.0 vs. Postpartum 13.7 ± 2.8cm/sec, p < 0.001), unlike their genetic positive (G+) counterparts (Mitral e’ Entry: 10.5 ± 1.7 vs. Postpartum 10.8 ± 2.4cm/sec, p = 0.853). ConclusionsPostpartum recovery of heart function after severe PreE is attenuated in women with deleterious cardiomyopathic genetic polymorphisms.

EGR1 modulates EPHB4-induced trophoblast dysfunction in recurrent spontaneous abortion†.

Recurrent spontaneous abortion, defined as at least three unexplained abortions occurring before the 20-24 week of pregnancy, has a great impact on women's quality of life. Ephrin receptor B4 has been associated with trophoblast function in preeclampsia. The present study aimed to verify the hypothesis that ephrin receptor B4 regulates the biological functions of trophoblasts in recurrent spontaneous abortion and to explore the upstream mechanism. Ephrin receptor B4 was overexpressed in mice with recurrent spontaneous abortion. Moreover, ephrin receptor B4 inhibited trophoblast proliferation, migration, and invasion while promoting apoptosis. Downregulation of early growth response protein 1 expression in mice with recurrent spontaneous abortion led to ephrin receptor B4 overexpression. Poor expression of WT1-associated protein in mice with recurrent spontaneous abortion reduced the modification of early growth response protein 1 mRNA methylation, resulting in decreased early growth response protein 1 mRNA stability and expression. Overexpression of WT1-associated protein reduced the incidence of recurrent spontaneous abortion in mice by controlling the phenotype of trophoblasts, which was reversed by early growth response protein 1 knockdown. All in all, our findings demonstrate that dysregulation of WT1-associated protein contributes to the instability of early growth response protein 1, thereby activating ephrin receptor B4-induced trophoblast dysfunction in recurrent spontaneous abortion. Our study provides novel insights into understanding the molecular pathogenesis of recurrent spontaneous abortion.

Characteristics of liver function in patients with preeclampsia

BACKGROUND:Despite a significant number of studies devoted to the problem of preeclampsia, to date, a large number of issues related to the etiology, pathogenesis, and therapy for this pathology remain far from a final solution. That is why obstetricians always face the difficult task of developing rational tactics for the management and delivery of pregnant women with preeclampsia, one has to take into account all the risks to the health of both the mother and her unborn child. Therefore, relevant is the search for the most informative methods for diagnosing liver dysfunction with an increase in the severity of preeclampsia. The hepatobiliary system is known to carry a multifunctional load during gestation and is one of the first to respond to an increase in the severity of preeclampsia. It is, therefore, crucial to choose priority biochemical parameters of blood that reflect liver function in preeclampsia, which can be used as additional criteria for making an obstetric decision in order to prevent maternal and perinatal complications.&#x0D; AIM: The aim of this study was to analyze alterations in liver function in preeclampsia, in order to determine the criteria for the development of hepatic cell insufficiency as indicators of the transition to severe preeclampsia and multiple organ failure.&#x0D; MATERIALS AND METHODS:This study included 123 pregnant women, of which group I (n= 40) consisted of pregnant women with preeclampsia without changes in liver function, group II (n= 33) was made up of pregnant women with preeclampsia and impaired liver function, while group III (n= 50) only comprised pregnant women with normal pregnancy. All pregnant women underwent a biochemical blood test with the determination of the parameters of cytolysis (aspartate aminotransferase, alanine aminotransferase, glutamate dehydrogenase, De Ritis ratio), cholestasis (alkaline phosphatase, total and direct bilirubin, gamma-glutamyl transpeptidase, bile acids), and hepatic cell insufficiency (cholinesterase, total protein, albumin, urea, lactate dehydrogenase), as well as a clinical blood test and coagulation tests. Pregnant women with preeclampsia were observed in the intensive care unit, with vital functions monitored.&#x0D; RESULTS: The leading syndrome complex with increasing severity of preeclampsia was the cytolytic one, in which the levels of transaminases increased moderately with a predominance of alanine aminotransferase over aspartate aminotransferase activities (the De Ritis ratio was lesser than 1.0). With the development of hepatic cell insufficiency, aspartate aminotransferase activity dominated over alanine aminotransferase one (the De Ritis ratio was greater than 1.33). We also found an increase in glutamate dehydrogenase and lactate dehydrogenase activities and, among the cholestatic parameters, in the level of direct bilirubin. Hepatic cell insufficiency was characterized by a decrease in the activity of cholinesterase and decreased total protein and albumin concentrations. In the group of pregnant women with preeclampsia, we found a decrease in hemoglobin and platelet counts.&#x0D; CONCLUSIONS:Altered liver function in preeclampsia reflects an increase in the severity of the pathology and indicates the development of multiple organ failure. In its terminal stage, all syndrome complexes manifest themselves as cytolytic, cholestatic and hepatic cell insufficiencies.

HDAC4 regulates the proliferation, migration, and invasion of trophoblasts in pre-eclampsia through the miR-134-5p/FOXM1 axis.

Epigenetics, including histone modifications and noncoding RNAs, affects abnormal placental function in pre-eclampsia (PE). This study was conducted to explore the role of histone deacetylase 4 (HDAC4) in trophoblast invasion and migration. The expression levels of HDAC4, microRNA (miR)-134-5p, and forkhead box protein M1 (FOXM1) in placentas from PE patients and healthy controls and their correlations were examined. HTR8/SVneo cells were cultured and underwent gene intervention. Then, trophoblast proliferation, invasion, and migration were evaluated by 5-ethynyl-2'deoxyuridine, Transwell, and scratch assays. The enrichments of HDAC4 and acetylated histone H3 at lysine 9 (H3K9Ac) on the miR-134-5p promoter were quantified by chromatin immunoprecipitation. The binding of miR-134-5p to FOXM1 was analyzed by dual-luciferase assay. HDAC4 and FOXM1 were downregulated while miR-134-5p was upregulated in PE placentas. HDAC4 downregulation impaired trophoblast proliferation, invasion, and migration while HDAC4 overexpression played the opposite role. Mechanically, HDAC4 deacetylated H3K9Ac to repress miR-134-5p expression by erasing H3K9Ac, reduced the binding of miR-134-5p to FOXM1, and then promoted FOXM1 transcription. miR-134-5p overexpression or FOXM1 downregulation abrogated the promotive role of HDAC overexpression in trophoblast invasion and migration. Our study unraveled a novel mechanism of trophoblast proliferation, invasion, and migration and proposed that HDAC4 may be a promising target for the treatment of PE.

MicroRNA-378a-3p plays a regulatory role in trophoblast cell function in preeclampsia by targeting CMTM3

BackgroundPreeclampsia (PE) is a potential multisystemic disease in the middle and late pregnancy. Although its precise etiology and pathogenesis remain unknown, it is a significant cause of morbidity and mortality in both pregnant women and newborns. This study explored the effects of the miR-378a-3p/CKLF-like MARVEL transmembrane domain containing 3 (CMTM3) upon the trophoblast biological functions in PE. MethodsThe placental pathology of PE were identified by hematoxylin-eosin (HE) staining, and miR-378a-3p expression in placental tissues of PE was verified by RT-qPCR. Trophoblast cells (HTR-8/SVneo and JEG-3) were treated with lipopolysaccharide (LPS), and cell counting kit-8 (CCK-8) assay, flow cytometry, scratch assay, and Transwell assay were carried out to measure cell viability, apoptosis, migratory and invasive capacities, respectively. Western blot was performed to determine the expression levels of the cell migration-related proteins. The binding of miR-378a-3p to CMTM3 was verified through a dual-luciferase reporter gene assay. ResultsmiR-378a-3p expression levels were down-regulated in placental tissues and primary trophoblast cells from women with PE compared to the control group. The overexpression of miR-378a-3p promoted the capabilities of LPS-treated trophoblast cells to proliferate, migrate and invade. In contrast, it impeded cell apoptosis, promoted matrix metallopeptidase (MMP)-2 and MMP-9 expression and inhibiting TIMP metallopeptidase inhibitor (TIMP)-1 and TIMP-2 expression. Regarding the molecular mechanism, miR-378a-3p was chosen as the target to modulate the expression level of CMTM3. CMTM3 expression was increased in placental tissues and primary trophoblast cells from women with PE compared to the control group. CMTM3 overexpression could partially neutralize the effects of the overexpressed miR-378a-3p on trophoblast cell function and the expression levels of migration-associated proteins. ConclusionOur study provides a foundation for miRNA-targeted therapy for preeclampsia by establishing for the first time a potential role for the miR-378a-3p/CMTM3 axis in regulating trophoblast cell activities by altering the expression of migration-related proteins.

Evaluation of Fetal Cardiac Functions in Preeclampsia: Does the Severity or Proteinuria Affect Fetal Cardiac Functions?

To compare the fetal cardiac functions in preeclampsia and control group, and determine whether the severity or amount of proteinuria affects fetal cardiac functions. This prospective case-control study involves 48 pregnant women with preeclampsia and 48 healthy women. Pulsed wave Doppler, M-mode, and tissue Doppler imaging were used to measure the cardiac function between the 32 and 34 gestational weeks in each group. All Doppler indices and cardiac function parameters were also compared in subgroups with mild and severe preeclampsia and between subgroups with proteinuria >3 g/24 hours and <3 g/24 hours. Decreased diastolic function (decreased E, A, E', and A' values in mitral/tricuspid valves and increased isovolumetric relaxation time) and decreased systolic functions (decreased mitral and tricuspid annular plane systolic excursion and S' value in mitral/tricuspid valves) were detected in the preeclampsia group. Decreased tricuspid E value in severe preeclampsia compared with mild preeclampsia was shown in the present study. Preeclampsia may cause changes in systolic and diastolic functions in the fetal heart. Subclinical functional changes of these fetuses can be detected earlier and more sensitively with the help of tissue Doppler imaging. Biventricular diastolic functional changes are more prominent in preeclamptic cases with proteinuria >3 g/24 hours.

Creating the Phenotype of Preeclamptic Endothelial Dysfunction in Placental Vessels

Objective: To determine if placental vessel endothelial dysfunction can be produced in control vessels by exposure to preeclamptic plasma, establishing a model to further explore the mechanisms of dysfunction and therapeutics to restore function in preeclampsia. Hypothesis: Preeclamptic plasma administered to unaffected vessels induces endothelial dysfunction. Methods: Placental microvessels were dissected from the maternal side of placentas from patients consented to the Medical College of Wisconsin Maternal Research Placenta and Cord Blood Bank. Control vessels were treated with 10% healthy maternal plasma or 10% preeclamptic (PreE) maternal plasma within the vessel lumen for 12-16 hours[MJ1]. PreE vessels were not treated with plasma. Microvessels were then cannulated on glass micropipettes, pressurized to 60mmHg and constricted with 0.1-1.0 nM Endothelin-1 (ET-1). A 1-100cm H2O pressure gradient was applied and the inner diameter of the vessel was measured by video microscopy. The change in diameter was calculated as a % of maximum diameter as assessed by exposure to 100μM papaverine. Flow mediated dilation (FMD) was evaluated by a two-way ANOVA test with Dunnett’s multiple comparisons. The maximum dilation values were evaluated by a Kruskal-Wallis test with Dunn’s multiple comparative test or t-test as appropriate. FMD is evaluated as mean +/- SEM. Data: Control vessels at maximum flow dilated to 81.1 % ± 7.1 % (n=5), whereas vessel from PreE placentas dilated to 36.9 % ± 8.6% (n=3,). Incubation of control vessels with normal plasma resulted in maximal dilation of 80.6% ± 3.3%, n=3. Control vessels incubated with plasma from PreE patients dilated to 44.7% ± 4.7%. n=3). Summary of Results: Control vessels dilated significantly more than PreE vessels when evaluated by t-test (p=0.05). Incubation of control vessels with normal plasma did not change maximal dilation (p&gt;0.99). Control vessels incubated with PreE plasma demonstrated a near significant drop in dilatory capacity (p=0.05). PreE plasma exposed vessels compared to untreated PreE vessels showed no significant difference (p=0.46[DDG2] ).When comparing overall flow mediated dilatory responses in these vessels there is a significant difference observed between control vessels, control vessels treated with PreE plasma, and PreE vessels at 50cm H2O (p&lt;0.05). This difference is even more significant (p&lt;0.01) at the maximum pressure gradient when analyzed by two-way ANOVA. There is no significant difference at any point between control vessels and control vessels treated with normal plasma as evaluated by two-way ANOVA (p&gt;0.99). Conclusions: The addition of PreE plasma to control vessels demonstrates similar impairment in endothelium-dependent vasodilation as seen in untreated PreE vessels. Future directions will include evaluation of the mechanisms of vasodilation and therapeutic options that could restore endothelial function in PreE vessels. NHLBI 1K08HL150340-01 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

RISING STARS: Approaches to modeling placental function in preeclampsia in vitro and in vivo.

Modeling preeclampsia remains difficult due to the nature of the disease and the unique characteristics of the human placenta. Members of the Hominidae superfamily have a villous hemochorial placenta that is different in structure from those of other therian mammals, including the mouse hemochorial placenta, making this common animal model less ideal for studying this disease. Human placental tissues delivered from pregnancies complicated by preeclampsia are excellent for assessing the damage the disease causes but cannot answer how or when the disease begins. Symptoms of preeclampsia manifest halfway through pregnancy or later, making it currently impossible to identify preeclampsia in human tissues obtained from an early stage of pregnancy. Many animal and cell culture models recapitulate various aspects of preeclampsia, though none can on its own completely capture the complexity of human preeclampsia. It is particularly difficult to uncover the cause of the disease using models in which the disease is induced in the lab. However, the many ways by which preeclampsia-like features can be induced in a variety of laboratory animals are consistent with the idea that preeclampsia is a two-stage disease, in which a variety of initial insults may lead to placental ischemia, and ultimately systemic symptoms. The recent development of stem cell-based models, organoids, and various coculture systems have brought in vitro systems with human cells ever closer to recapitulating in vivo events that lead to placental ischemia.

A novel in vitro stem cell model to study maternal endothelial function in preeclampsia

A novel in vitro stem cell model to study maternal endothelial function in preeclampsia

Preeclampsia: Maternal cardiovascular function and optimising outcomes

Preeclampsia is associated with cardiac dysfunction, not only during the clinical phase of the disease, but also after delivery, with long term implications for both maternal and neonatal cardiovascular health. An abnormal cardiovascular phenotype also precedes conception, indicating that pre-existing cardiovascular dysfunction is associated with the development of preeclampsia. This review summarises the changes in cardiovascular function in preeclampsia, examining the evidence for when cardiovascular dysfunction develops and presenting the evidence for two phenotypes – one associated with fetal growth restriction, low cardiac output and high peripheral resistance, and a second associated with normal fetal growth, high cardiac output and low peripheral resistance. The presence of a cardiovascular phenotype that precedes conception demonstrates the potential for prevention of preeclampsia through cardiovascular optimisation at this stage. The two phenotypes mean therapy can be targeted to optimising cardiovascular function. The prevention and effective treatment of preeclampsia are essential aspects of improving maternal and neonatal cardiovascular health in the long term.

Deep metagenomic characterization of gut microbial community and function in preeclampsia.

Preeclampsia (PE) is a pregnancy complication characterized by severe hypertension and multiple organ damage. Gut microbiota has been linked to PE by previous amplicon sequencing studies. To resolve the PE gut microbiota in a higher taxonomy resolution, we performed shotgun metagenomic sequencing on the fecal samples from 40 early-onset PE and 37 healthy pregnant women. We recovered 1,750 metagenome-assembled genomes (representing 406 species) from the metagenomic dataset and profiled their abundances. We found that PE gut microbiota had enriched in some species belonging to Blautia, Pauljensenia, Ruminococcus, and Collinsella and microbial functions such as the bacitracin/lantibiotics transport system, maltooligosaccharide transport system, multidrug efflux pump, and rhamnose transport system. Conversely, the gut microbiome of healthy pregnant women was enriched in species of Bacteroides and Phocaeicola and microbial functions including the porphyrin and chlorophyll metabolism, pyridoxal-P biosynthesis, riboflavin metabolism, and folate biosynthesis pathway. PE diagnostic potential of gut microbial biomarkers was developed using both species and function profile data. These results will help to explore the relationships between gut bacteria and PE and provide new insights into PE early warning.

Is there a role of proinflammatory cytokines on degenerin-mediated cerebrovascular function in preeclampsia?

Preeclampsia (PE) is associated with adverse cerebrovascular effects during and following parturition including stroke, small vessel disease, and vascular dementia. A potential contributing factor to the cerebrovascular dysfunction is the loss of cerebral blood flow (CBF) autoregulation. Autoregulation is the maintenance of CBF to meet local demands with changes in perfusion pressure. When perfusion pressure rises, vasoconstriction of cerebral arteries and arterioles maintains flow and prevents the transfer of higher systemic pressure to downstream microvasculature. In the face of concurrent hypertension, loss of autoregulatory control exposes small delicate microvessels to injury from elevated systemic blood pressure. While placental ischemia is considered the initiating event in the preeclamptic cascade, the factor(s) mediating cerebrovascular dysfunction are poorly understood. Elevated plasma proinflammatory cytokines, such as tumor necrosis factor α (TNF‐α) and interleukin‐17 (IL‐17), are potential mediators of autoregulatory loss. Impaired CBF responses to increases in systemic pressure are attributed to the impaired pressure‐induced (myogenic) constriction of small cerebral arteries and arterioles in PE. Myogenic vasoconstriction is initiated by pressure‐induced vascular smooth muscle cell (VSMC) stretch. Recent studies from our laboratory group indicate that proinflammatory cytokines impair the myogenic mechanism of CBF autoregulation via inhibition of vascular degenerin proteins, putative mediators of myogenic constriction in VSMCs. This brief review links studies showing the effect of proinflammatory cytokines on degenerin expression and CBF autoregulation to the pathological cerebral consequences of preeclampsia.

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.

Analysis of perinatal coagulation function in preeclampsia.

To study the dynamic changes in perinatal coagulation function in patients with preeclampsia (PE).The general data and coagulation indexes of 290 PE patients during the perinatal period (prenatal and 1 and 3 days postpartum) and 256 healthy pregnant women in the third trimester of pregnancy were investigated, and the data were analyzed.Compared with healthy pregnant women, prothrombin time (PT), fibrinogen (FIB), platelet count (PLT), mean platelet volume (MPV), thrombocytocrit (PCT), maximum amplitude (MA), and coagulation index (CI) of PE patients decreased, and activated partial thrombin time (APTT), thrombin time (TT), D-dimer (DD), platelet distribution width (PDW) and K values increased before delivery (P < .05). APTT and FIB in PE patients were lower in the day 1 postpartum group than in the prenatal and postpartum day 3 groups, and TT, DD, and fibrin degradation products (FDP) were higher (P < .05). PCT and MPV were highest in the prenatal group (P < .05).Compared with that of healthy pregnant women, the coagulation function of PE patients is in a relatively low-coagulation and high-fibrinolysis state on postpartum day 1, which increases the risk of postpartum hemorrhage and other adverse outcomes.

Silencing lncRNA-DGCR5 increased trophoblast cell migration, invasion and tube formation, and inhibited cell apoptosis via targeting miR-454-3p/GADD45A axis.

Long noncoding RNA (lncRNA)-DGCR5 has been recognized as a potential tumor progression regulator, while its expression and specific functions in preeclampsia (PE) development remain unveiled. The expressions of miR-454-3p, lncRNA-DiGeorge syndrome critical region gene 5 (DGCR5) and growth arrest and DNA damage protein-inducible 45A (GADD45A) in placental tissues from PE patients or HTR-8/SVneo cells were assessed by Western blot or qRT-PCR. Dual-luciferase reporter assay determined the binding relations between miR-454-3p and GADD45A and between miR-454-3p and lncRNA-DGCR5. The viability, apoptosis, migration, invasiveness and tube formation of HTR-8/SVneo cell were evaluated using cell counting kit (CCK)-8, Annexin-V/Propidium iodide staining, wound healing, transwell and tube formation assays, respectively. miR-454-3p was low-expressed in PE tissue, and upregulation of miR-454-3p increased viability and promoted migration, invasion and tube formation in HTR-8/SVneo cells while inhibiting apoptosis. Then, miR-454-3p was found to directly target GADD45A which was high-expressed in PE tissues. Overexpressing GADD45A decreased the viability and inhibited the migration, invasion and tube formation of HTR-8/SVneo cells while enhancing apoptosis, and it neutralized the effect of miR-454-3p upregulation. In turn, miR-454-3p upregulation reversed the effect of GADD45A overexpression. Meanwhile, miR-454-3p could also target lncRNA-DGCR5. Silencing lncRNA-DGCR5 increased miR-454-3p expression and cell viability and promoted migration, invasion and tube formation in HTR-8/SVneo cells while inhibiting apoptosis, and it counteracted the effect of miR-454-3p downregulation. As usual, miR-454-3p downregulation reversed the effect of lncRNA-DGCR5 silencing. To conclude, silencing lncRNA-DGCR5 increased viability, promoted migration, invasion and tube formation, and inhibited apoptosis in HTR-8/SVneo cells by rescuing the inhibition of GADD45A expression caused by miR-454-3p.

Association between Serum Albumin and Hypothyroidism in Preeclampsia: A Case-control Study

Introduction: Preeclampsia is a cause of high morbidity and mortality in pregnant women. Serum albumin is found to be low in preeclampsia. Few recent studies have shown a state of hypothyroidism in preeclampsia. Aim: To find the association between the serum albumin and thyroid hormone levels in preeclampsia and seek to find if hypoalbuminemia increases the risk of hypothyroidism. Materials and Methods: A case-control study was done at Department of Biochemistry and the Department of Obstetrics and Gynaecology of Government Medical College, Thiruvananthapuram, Kerala, with 40 preeclampsia cases and 40 normal pregnant controls, in 30-38 week gestation. Serum albumin and thyroid profile-Total T3, Total T4, Thyroid Stimulating Hormone (TSH), freeT3 (fT3), freeT4 (fT4) were tested. Statistical analysis was done with Student’s t-test, Chi-square, Fischer’s t-test and Pearson’s correlation coefficients. Results: The mean serum albumin was significantly lesser in preeclampsia (3.11±0.39) than in controls (3.7±0.14 g/dL). Thyroid hormones were significantly decreased in preeclampsia. TSH was significantly raised (3.76±1.55 mIU/L) in preeclampsia compared to normal pregnant ladies (2.3±0.94 mIU/L). In cases with hypoalbuminemia, risk for hypothyroidism was 2.85 times compared to those with normal albumin but was not statistically significant. In severe preeclampsia, there was a two times increased risk. There was a negative correlation of TSH and positive correlation for fT4 with serum albumin. However, this was statistically not significant. Conclusion: Hypothyroidism in preeclampsia was not significantly correlated with hypoalbuminemia in this study. Thus hypoalbuminemia did not significantly increase the risk for hypothyroidism in our study. Further studies are needed to determine the risk factors affecting thyroid function in preeclampsia.

Comparative Long-chain Polyunsaturated Fatty Acids Levels in Blood, Placenta and Cord Blood of Pregnant Women with or without Pre-eclampsia

Background and Objective: Long-chain polyunsaturated fatty acids (LCPUFA) play an important role in the regulation of fat metabolism in the placenta and fetus. Changes in placental function in pre-eclampsia affect the transport of fatty acids and affect fetal nutrition. The aim of the study was to compare LCPUFA levels in blood, placenta and cord blood of pregnant women with or without pre-eclampsia. Methods: The blood, placenta and umbilical cord blood of pregnant women (n = 30 each) who were normotensive and with pre-eclampsia were collected. The levels of fatty acids in maternal blood, placenta and umbilical cord blood were determined by the quartz capillary gas chromatography technique. Results: The average age of normal pregnant women was 27.0±4.5 years and that of pre-eclampsia pregnant women was 30±4.0 years (P &gt; 0.05). The levels of total fatty acids, arachidonic acid (AA) and docosahexaenoic acid (DHA) were higher in pregnant women with pre-eclampsia than in normal women. The level of linoleic acid in cord blood and placenta was significantly higher in pre-eclampsia group than in the normal pregnant women while linoleic acid content in maternal blood being lower in pre-eclampsia group compared to the normal maternal group. Conclusion: The changes of LCPUFA in blood, placenta and umbilical blood of pre-eclampsia may be related to the changes of LCPUFA in placenta. These changes may be involved in the pathophysiological process of pre-eclampsia. Maternal supplement of LCPUFA, such as DHA, in early gestation may be helpful in improving morbidity associated with maternal eclampsia.