Placental Hypoxia Research Articles

Advances in biomarker development and potential application for preeclampsia based on pathogenesis.

Preeclampsia (PE) is a pregnancy-specific complication that seriously threatens the health and safety of mothers and infants. The etiology of PE has not been fully elucidated, and no effective treatments are currently available. A pregnant woman with PE often has to make a tough choice on either endangering her own health to give a birth or being forced to terminate her pregnancy. It is recommended by the International Federation of Gynecology and Obstetrics that the combination of maternal high-risk factors and biomarkers could form a good strategy for predicting the risk of PE. Such a combination may also enable more effective monitoring and early clinical intervention in high-risk populations to reduce the risk of PE. Therefore, biomarkers validated by extensive clinical research may be formally applied for clinical PE risk prediction. In this review, we summarized data from clinical research on potential biomarkers and classified them according to the current four major hypotheses, namely placental or trophoblast ischemia and hypoxia, vascular endothelial injury, oxidative stress, and immune dysregulation. Additionally, we also discussed the underlying mechanisms by which these potential biomarkers may be involved in the pathogenesis of PE. Finally, we propose that multiple biomarkers reflecting different aspects of the disease pathogenesis should be used in combination to detect the high-risk PE population in support of clinically targeted intervention and prevention of PE. It is expected that tests made of more sensitive and reliable PE biomarkers based on the aforementioned major hypotheses could potentially improve the accuracy of PE prediction in the future.

Influenza A virus causes maternal and fetal pathology via innate and adaptive vascular inflammation in mice

Influenza A virus (IAV) infection during pregnancy causes severe maternal and perinatal complications, despite a lack of vertical transmission of IAV across the placenta. Here, we demonstrate a significant alteration in the maternal vascular landscape that underpins the maternal and downstream fetal pathology to IAV infection in mice. In IAV infection of nonpregnant mice, the local lung inflammatory response was contained to the lungs and was self-resolving, whereas in pregnant mice, virus dissemination to major maternal blood vessels, including the aorta, resulted in a peripheral "vascular storm," with elevated proinflammatory and antiviral mediators and the influx of Ly6Clow and Ly6Chigh monocytes, plus neutrophils and T cells. This vascular storm was associated with elevated levels of the adhesion molecules ICAM and VCAM and the pattern-recognition receptors TLR7 and TLR9 in the vascular wall, resulting in profound vascular dysfunction. The sequalae of this IAV-driven vascular storm included placental growth retardation and intrauterine growth restriction, evidence of placental and fetal brain hypoxia, and increased circulating cell free fetal DNA and soluble Flt1. In contrast, IAV infection in nonpregnant mice caused no obvious alterations in endothelial function or vascular inflammation. Therefore, IAV infection during pregnancy drives a significant systemic vascular alteration in pregnant dams, which likely suppresses critical blood flow to the placenta and fetus. This study in mice provides a fundamental mechanistic insight and a paradigm into how an immune response to a respiratory virus, such as IAV, is likely to specifically drive maternal and fetal pathologies during pregnancy.

Galectin Family in Placental Insufficiency Syndromes

Galectin Family in Placental Insufficiency Syndromes

Abstract P208: Imaging The Longitudinal Reduction In Placental Ischemia In Response To Therapeutic Intervention For Preeclampsia

Preeclampsia is believed to be induced by abnormal vascular remodeling and the resulting placental ischemia during early development. Sildenafil, a phosphodiesterase-5 inhibitor, reduces the maternal symptoms of preeclampsia by promoting angiogenesis and enhancing NO-mediated vasodilation. However, the effect of sildenafil on in vivo placental function has not been demonstrated. We performed longitudinal spectral photoacoustic (sPA) imaging of placental therapeutic response to sildenafil in the reduced uterine perfusion pressure (RUPP) model of preeclampsia. Sprague Dawley rats were administered sildenafil (S) via drinking water beginning on gestational day (GD) 11. Imaging was performed on GD14, 16, and 18 with the RUPP procedure implemented after the first imaging session. sPA images of oxygenation show that the placental ischemia induced by the RUPP surgery (RUPP, n=8, 48%; NP, n=8, 54%), was effectively eliminated by treatment with sildenafil (RUPP+S, n=8, 53%, p<0.05). In addition to improved placental oxygenation, sildenafil was also found to reduce mean arterial pressure in RUPP animals by GD18 (RUPP, 110 mmHg; RUPP+S, 98 mmHg; p<0.05), consistent with prior reports. Our studies demonstrate that sPA imaging can detect changes in placental oxygenation which could be used to indicate in vivo placental therapeutic response. Figure 1: Placental hypoxia in the RUPP is improved by treatment with sildenafil on GD16. B-mode US images (a, c) of anatomy were used to manually select the placenta (p) and average placental oxygenation was calculated. A custom red-blue oxygenation colormap was then overlaid for visualization (b, d). Scale bars = 3mm.

EVALUATION OF LEFT VENTRICULAR SYSTOLIC PARAMETERS IN PRE-ECLAMPTIC WOMEN

Objective: to study systolic parameters with echocardiography in pre-eclampsia. Pre-eclampsia is a multisystem disorder of unknown etiology. The underlying pathophysiological mechanism is to be impaired torphoblastic invasion of spiral arteries with placental hypoperfusion and hypoxia.
 Methods: This was a hospital based prospective case control study carried out in Department of Obstetrics & Gynaecology in SMS Medical College, Jaipur during the period of June 2018 to Aug 2019. 60 women enrolled inthe study after applying inclusion and exclusion criteria. All women underwent 2D-echocardiography. Cardiac systolic parameters were recorded and compared.
 Results: 2D-echocardiography revealed impairment in form of mean LVESV in pre-eclamptic women was 35.73 ± 0.70 mL, mean stroke volume was 63.50 ± 13.26 mL when compared to normotensive women LVESV 33.40 ± 0.63 ml (p = 0.04) and stroke volume was 53.96 ± 9.46 mL (p = 0.02).
 Conclusion: To identifying pre-eclamptic patients who are at higher risk of developing cardiovascular complication later in life by non-invasive 2D-echocardiography.
 Keywords: Echocardiography, Systolic parameters, Stroke volume, Left ventricular end systolic

Stillbirth in women with diabetes: a retrospective analysis of fetal autopsy reports

Introduction Diabetes in pregnancy is associated with an increased rate of stillbirth. There are a wide variety of factors that have been implicated including placental insufficiency, hypoxia, hyperinsulinemia and impaired cardiac function. Furthermore, there is evidence that diabetic pregnancies have an increased rate of fetal cardiomyopathy as compared to non-diabetic pregnancies. Prior studies have indicated that this association can also be an etiology for diabetic stillbirth. The purpose of this study was to determine if diabetic pregnancies have an increased risk of fetal cardiomyopathy identified on fetal autopsy as compared to non-diabetic women with a stillbirth in a cohort of pregnancies that had evaluation with a fetal autopsy. Materials and methods Retrospective cohort study of women with a stillbirth who consented to fetal autopsy at an academic medical center from 2011 to 2017. Stillbirth was defined as an intrauterine fetal demise at ≥20 weeks’ gestation. Women with diabetes defined as pre-gestational diabetes type 1, pre-gestational diabetes type 2, and gestational diabetes were compared to women without diabetes. Primary outcome was fetal cardiomyopathy. Other etiologies for stillbirth were also evaluated and classified according to the Stillbirth Collaborative Research Network (SCRN) initial causes of fetal death. Fisher exact test, χ2 test, and Mann Whitney U tests were performed as appropriate, with p < .05 considered significant. Generalized linear models were performed for fetal organ weights controlling for gestational age of delivery, maternal chronic hypertension, delivery body mass index, and birthweight. Results A total of 78 women elected to have fetal autopsy examinations during the study period. Of these, 75 had complete information available for review. A total of 60 women did not have diabetes and 15 women had diabetes. Of pregnancies complicated by diabetes, 11 had insulin dependent diabetes and 4 had non-insulin dependent diabetes. Fetal cardiomyopathy was diagnosed on autopsy for 7 (46.7%) of pregnancies with diabetes and 2 (3.3% of pregnancies without diabetes (RR 14.00 [95% CI 3.23–60.65], p < .001). These associations were still significant even when analyzing only those pregnancies without fetal congenital heart disease (7 [46.7%] diabetic pregnancies with cardiomyopathy versus 1 [2.0%] nondiabetic pregnancy with cardiomyopathy, RR 23.80 [95% CI 3.17–178.46], p < .001). There was no difference between diabetic and non-diabetic pregnancies in regards to other causes for stillbirth. Stillbirths in pregnancies with diabetes also had larger fetal heart, liver, and adrenal weights on fetal autopsy. Conclusion Women with diabetes have 14 times the risk of fetal cardiomyopathy identified at fetal autopsy as compared to women without diabetes. As the prediction and prevention of diabetic stillbirth is limited, information on potential causes of stillbirth may help future research identify those pregnancies at the greatest risk for adverse outcome.

Clinical Implications of Epigenetic Dysregulation in Perinatal Hypoxic-Ischemic Brain Damage.

Placental and fetal hypoxia caused by perinatal hypoxic-ischemic events are major causes of stillbirth, neonatal morbidity, and long-term neurological sequelae among surviving neonates. Brain hypoxia and associated pathological processes such as excitotoxicity, apoptosis, necrosis, and inflammation, are associated with lasting disruptions in epigenetic control of gene expression contributing to neurological dysfunction. Recent studies have pointed to DNA (de)methylation, histone modifications, and non-coding RNAs as crucial components of hypoxic-ischemic encephalopathy (HIE). The understanding of epigenetic dysregulation in HIE is essential in the development of new clinical interventions for perinatal HIE. Here, we summarize our current understanding of epigenetic mechanisms underlying the molecular pathology of HI brain damage and its clinical implications in terms of new diagnostic, prognostic, and therapeutic tools.

Transcription factor AP2A affects sFLT1 expression and decidualization in decidual stromal cells: Implications to preeclampsia pathology

Preeclampsia (PE) yields a spectrum of phenotypic expression, leading to varying degrees of hypertension, maternal renal dysfunction and placental insufficiency with resultant maternal and neonatal morbidity. Increased sFLT1 expression contributing to angiogenic factor imbalance, placental hypoxia, failed immune adaptation to the fetus and defective decidualization are among the commonly proposed theories of PE pathogenesis. Recently researchers have focused their attention on the events that occur at the maternal fetal interface as potential contributors to PE pathogenesis. Decidual stromal cells (DSC) isolated from preeclamptic women show diminished ability to decidualize upon stimulation and reduced capacity to downregulate sFlt-1 levels. In this study, we sought to gain insight into the molecular mechanism(s) involved in the aberrant decidualization capacity of PE DSC. Our findings using qRT-PCR show that PE DSCs have 6-fold higher basal levels of transcription factor AP2A (TFAP2A) RNA compared to women without PE and that expression of TFAP2A increases during decidualization but only in DSCs of normotensive (NT) women. Silencing of TFAP2A using Trilencer siRNA upregulated sFLT1 expression only in NT-DSCs but suppressed the expression of decidualization markers PRL, IGFBP1 and their regulator FOXO1 in cells from both groups. Collectively, our observations suggest that TFAP2A acts as a repressor of sFLT1 and plays a necessary role in decidualization possibly through interacting with another factor that is aberrantly expressed in PE DSCs.

Circular RNA circ_0111277 attenuates human trophoblast cell invasion and migration by regulating miR-494/HTRA1/Notch-1 signal pathway in pre-eclampsia

Mounting evidence has revealed that impaired spiral artery remodeling, placental dysfunction, and inadequate trophoblast invasion are closely correlated with the etiology and pathogenesis of pre-eclampsia (PE). Moreover, defective trophoblast invasion may trigger poor maternal–fetal circulation and placental hypoxia, leading to PE. However, the detailed molecular pathology of PE remains unclear. Although circRNAs, as a new type of stable and abundant endogenous noncoding RNA, have been proven to be essential to the pathogenesis of various diseases, their role in PE requires further verification. In this context, it is necessary to unveil the roles of circRNAs in regulating the migration and invasion of extravillous trophoblasts. In this study, using quantitative real-time PCR, we confirmed that hsa_circ_0111277 was upregulated in PE placentas relative to the level in normal pregnancy placentas. In addition, positive correlations between hsa_circ_0111277 expression and PE-related factors (proteinuria level at 24 h and placental weight) were identified by Pearson’s analysis based on the clinical data of 25 PE patients. Moreover, fluorescence in situ hybridization analysis illustrated that circ_0111277 was preferentially localized within the cytoplasm. Mechanistically, circ_0111277 sponged hsa-miR-494-3p in trophoblast cells to attenuate the latter’s repression by regulating HTRA1/Notch-1 expression. In conclusion, trophoblast cell migration and invasion were shown to be promoted and modulated by the hsa_circ_0111277/miR-494-3p/HTRA1/Notch-1 axis, which provides useful insight for exploring a new therapeutic approach for PE.

Maternal erythrocyte ENT1-mediated AMPK activation counteracts placental hypoxia and supports fetal growth.

Insufficient O2 supply is frequently associated with fetal growth restriction (FGR), a leading cause of perinatal mortality and morbidity. Although the erythrocyte is the most abundant and only cell type to deliver O2 in our body, its function and regulatory mechanism in FGR remain unknown. Here, we report that genetic ablation of mouse erythrocyte equilibrative nucleoside transporter 1 (eENT1) in dams, but not placentas or fetuses, results in FGR. Unbiased high-throughput metabolic profiling coupled with in vitro and in vivo flux analyses with isotopically labeled tracers led us to discover that maternal eENT1-dependent adenosine uptake is critical in activating AMPK by controlling the AMP/ATP ratio and its downstream target, bisphosphoglycerate mutase (BPGM); in turn, BPGM mediates 2,3-BPG production, which enhances O2 delivery to maintain placental oxygenation. Mechanistically and functionally, we revealed that genetic ablation of maternal eENT1 increases placental HIF-1α; preferentially reduces placental large neutral aa transporter 1 (LAT1) expression, activity, and aa supply; and induces FGR. Translationally, we revealed that elevated HIF-1α directly reduces LAT1 gene expression in cultured human trophoblasts. We demonstrate the importance and molecular insight of maternal eENT1 in fetal growth and open up potentially new diagnostic and therapeutic possibilities for FGR.

Role of oxygen in fetoplacental endothelial responses: hypoxia, physiological normoxia, or hyperoxia?

During pregnancy, placental vascular growth, which is essential for supporting the rapidly growing fetus, is associated with marked elevations in blood flow. These vascular changes take place under chronic physiological low O2 (less than 2-8% O2 in human; chronic physiological normoxia, CPN) throughout pregnancy. O2 level below CPN pertinent to the placenta results in placental hypoxia. Such hypoxia can cause severe endothelial dysfunction, which is associated with adverse pregnancy outcomes (e.g., preeclampsia) and high risk of adult-onset cardiovascular diseases in children born to these pregnancy complications. However, our current knowledge about the mechanisms underlying fetoplacental endothelial function is derived primarily from cell models established under atmospheric O2 (~21% O2 at sea level, hyperoxia). Recent evidence has shown that fetoplacental endothelial cells cultured under CPN have distinct gene expression profiles and cellular responses compared with cells cultured under chronic hyperoxia. These data indicate the critical roles of CPN in programming fetal endothelial function and prompt us to re-examine the mechanisms governing fetoplacental endothelial function under CPN. Better understanding these mechanisms will facilitate us to develop preventive and therapeutic strategies for endothelial dysfunction-associated diseases (e.g., preeclampsia). This review will provide a brief summary on the impacts of CPN on endothelial function and its underlying mechanisms with a focus on fetoplacental endothelial cells.

Soluble (pro)renin receptor increased by hypoxia maintains oxidative metabolism in trophoblasts.

Elevated soluble (pro)renin receptor (s(P)RR) concentration in maternal blood is associated with gestational hypertension and preeclampsia. Placenta has abundant expression of (P)RR, and the binding of (P)RR with pyruvate dehydrogenase E1 beta subunit (PDHB) is reported to maintain oxidative metabolism. Thus, we hypothesized that placental hypoxia may increase (P)RR, and the increased (P)RR may preserve PDHB expression. Expression and functional analyses were performed using human placental trophoblast cells, mainly JAR cells. (P)RR co-immunoprecipitated and showed co-immunofluorescence with PDHB mainly in the mitochondria. Hypoxia treatment significantly increased intracellular s(P)RR protein expression, but secreted s(P)RR in the culture medium was decreased by hypoxia. Hypoxia treatment did not alter PDHB expression or activity in the basal condition, but when (P)RR was knocked down by siRNA, PDHB protein and activity were reduced by hypoxia. Acetyl-CoA, the product of PDH activity, was significantly reduced by hypoxia treatment with (P)RR siRNA. S(P)RR is generated from full-length PRR when cleaved by specific proteases. Protease inhibitor experiments suggested furin and site 1 protease as the enzymes generating s(P)RR in JAR cells, and only when treated by site 1 protease inhibitor, PF429242, PDHB protein showed a significant trend to decrease with hypoxia. In JAR cells, hypoxia increased intracellular s(P)RR, and (P)RR preserved the expression and function of PDHB during hypoxia. (P)RR may help maintain oxidative metabolism and efficient energy production during placental ischemia in hypertensive disorders of pregnancy.

Pericyte Coverage and Microvessel Caliber: Association with Smoking Status and Body‐Mass‐Index in Normal and Pre‐eclamptic Pregnancies

Pre‐eclampsia (PE) is a hypertensive disorder of pregnancy that is a major cause of maternal and fetal morbidity and mortality worldwide. Current evidence suggests that PE may result from shallow implantation of the developing fetus into the uterus, leading to abnormal formation of uteroplacental blood vessels. Pericytes play critical roles in neovessel formation and are thought to also have a role in blood flow regulation in microvascular networks. Little is known however about their function in the placenta and how this may be altered in disease. Here, we sought to determine whether differences exist in placental microvessel caliber or pericyte coverage between normal and PE pregnancies. We also examined whether modifiable risk factors might impact the observed phenotypes. Human placental tissue was obtained from normal and PE pregnancies (IRB protocol approved by Carilion Clinic). Tissue sections were antibody labeled, imaged by confocal microscopy, and assessed for vascular‐specific metrics. For comparative analysis, placental tissue from WT mice was sectioned, labeled, and imaged by confocal to optimize protocols and assess for pericyte localization. Measurements were collected using ImageJ/FIJI, and statistical analysis for human samples compared results from PE vs. normal controls. Researchers were blinded to disease state until after analysis was complete. Forty patients were enrolled in the study: 20 had normal pregnancies, and 20 had pregnancies complicated by PE. A significant difference (p &lt; 0.005) was found in gestational age at birth between groups. Pre‐eclampsia was associated with larger overall microvessel caliber, diminished capillary size for microvasculature associated with pericytes, and diminished pericyte number relative to controls. BMI and smoking status were both inversely correlated with pericyte number. The phenotypic changes observed in placental microvessels from PE pregnancies may be related to placental hypoxia and are associated with modifiable risk factors known to underlie other microvascular diseases.

Regulation of stanniocalcin-1 secretion by BeWo cells and first trimester human placental tissue from normal pregnancies and those at increased risk of developing preeclampsia.

Stanniocalcin‐1 (STC‐1) is a multi‐functional glycosylated peptide present in the plasma of healthy women postpartum and increased further in pregnancies complicated by preeclampsia. Although the STC‐1 gene is expressed by the placenta what regulates its secretion and from which cells at the feto‐maternal interface is unknown. Here, we demonstrate for the first time that the syncytiotrophoblast and cytotrophoblast are a major site of STC‐1 protein expression in first trimester placental tissue. Further, in response to low oxygen, first trimester chorionic villous tissue from pregnancies at increased risk of developing preeclampsia secreted significantly more STC‐1 than normal tissue under the same conditions. Using the human trophoblast cell line BeWo we have shown that low oxygen increased the secretion of STC‐1 but it required co‐stimulation with the Adenosine‐3', 5'‐cyclic monophosphate (cAMP) analogue, 8‐Bromo adenosine‐3', 5'‐cyclic monophosphate cAMP (8 Br‐cAMP) to reach significance. Inhibition of Hypoxia inducible factor 2α (HIF‐2α) and the Phosphatidylinositol‐3 kinase (PI3‐Kinase)/AKT/Serum and glucocorticoid‐induced kinase‐1(SGK‐1) pathway resulted in significant inhibition of STC‐1 secretion. As both low oxygen and cAMP are known to play a central role in placental function, their regulation of STC‐1 points to a potentially important role in the maintenance of a normal healthy pregnancy and we would hypothesize that it may act to protect against prolonged placental hypoxia seen in preeclampsia.

The mitochondrial Na+/Ca2+ exchanger enables mitochondrial calcium balance in placental vessel from preeclampsia

Placental ischaemia and hypoxia accelerate the development of preeclampsia. Although mitochondria could actively regulate Ca2+ signals and involves in sarcoendoplasmic reticulum (SR) Ca2+ release in smooth muscle. AIM: To investigate mitochondrial calcium responses to caffeine-induced Ca2+ release via ryanodine receptor (RyR) in placental vessels from preeclampsia. METHODS: Placenta was collected from normal pregnancy (N = 40) or preeclampsia (N = 30). Vascular tension was recorded using Power-Lab system. Total internal reflection fluorescent microscope (TIRFM) was used to recorded and analyzed the [Ca2+]m uptake and efflux. RESULTS: Caffeine-induced contraction was decreased both in placental artery and placental vascular smooth muscle cells (VSMCs) from preeclampsia, which was related to the mitochondrial dysfunction. Mitochondria in placental vessels from preeclampsia showed impaired [Ca2+]m efflux function. To understand the role of NCLX in preeclampsia, studies about on vascular smooth muscle cells under ischaemia and hypoxia was performed in the absence of overexpression NCLX or not. Cells under ischaemia and hypoxia showed mitochondrial dyfunction similar to placental vessel from preeclampsia.

The impact of circulating exosomes derived from early and late onset pre-eclamptic pregnancies on inflammatory cytokine secretion by BeWo cells

ObjectivesThe pathogenesis of pre-eclampsia (PE) is associated with significant maternal and neonatal complications, an increased inflammatory response, placental hypoxia, and endothelial dysfunction, coupled with differential exosomal release profiles with immune modulation effects. Hence, this study evaluated the impact of circulating exosomes derived from early and late-onset pre-eclamptic pregnancies on inflammatory cytokine secretion by BeWo cells. Study DesignExosomes were isolated from plasma obtained from early-onset pre-eclamptic (EOPE; n = 15), late-onset pre-eclamptic (LOPE; n = 15), and gestational age-matched normotensive pregnancies (N ≤ 33 weeks; n = 15 and N ≥ 34 weeks; n = 15). Human BeWo cells were treated with characterized and quantified exosomes (100 μg/mL exosomal protein per pregnant group) for 24 h. The immunoassay method was used to measure the concentration of IL-8, IL-10, leptin, and HIF-α. ResultsExosome administration from women with EOPE and LOPE increased IL-8 and decreased IL-10 expression in BeWo cells. ConclusionCumulatively, our data demonstrated that circulating exosomes from the placenta and activated immune cells potentially influence inflammatory cytokine production in pre-eclamptic pregnancies.

Increased hepcidin levels in preeclampsia: a protective mechanism against iron overload mediated oxidative stress?

Background Pregnancy is a metabolic state which demands increased iron bioavailability. While in preeclampsia, due to the placental vascular events there is an iron surplus environment along with inflammation and placental hypoxia. Routinely in India iron is supplemented to all pregnant women irrespective of their general physical condition. Hepcidin a regulator of iron metabolism protects the cells from iron mediated cytotoxicity. Objective To find out whether hepcidin gets induced as a protective mechanism in preeclampsia patients in order to combat the environment of iron overload, oxidative stress, and endothelial dysfunction. Methods A cross-sectional study with follow up was carried out in a South Indian Tamil population. Forty healthy pregnant women and forty preeclampsia patients in the gestational age 32 ± 4 weeks were recruited (n = 80). Biochemical analysis to assess the serum levels of the following were carried out (1) indices of iron homeostasis – serum iron, ferritin, transferrin, hepcidin, (2) endothelial dysfunction –serum assymetric dimethyl arginine (ADMA) (3) oxidative stress – Malon di aldehyde (MDA) and ferric reducing ability of plasma (FRAP). Kolmogorov-Smirnov test, Mann-Whitney U test, Spearman’s correlation, linear regression and ROCAUC analysis were performed to understand their relationship with each other. Results Levels of serum iron, ferritin, transferrin saturation, hepcidin, and MDA/FRAP ratio were elevated significantly in preeclampsia patients compared to controls, while serum transferrin levels were significantly decreased in them. Hepcidin levels showed a significant positive correlation with serum ADMA, and MDA/FRAP. Serum hepcidin, transferrin saturationand MDA/FRAP ratio is useful in differentiating pre-eclampsia patients from healthy pregnant women. Conclusion Iron supplementation in preeclampsia patients might have led to a state of iron overload, which might have caused oxidative stress and endothelial dysfunction in preeclampsia patients. The rise in hepcidin levels in this scenario may be viewed as a protective mechanism to combat the iron overload mediated cytotoxicity.

Effect of L- Arginin on Placental Hipoxia Inducible Factor -1-Alpha (HIF-1-A) Expression at Preeclampsia Mice Models

Background: Placental hypoxia is one of the theories that cause preeclampsia. In placental hypoxia of preeclampsia, there is an increase of Hipoxia Inducible Factor 1 Alpha (HIF-1-A) expression as a response to hypoxia. L-Arginine administration through the L-Arginine-Nitric Oxide pathway is expected to improve placental hypoxia. This study aimed to examine the effect of L- Arginin on placental HIF-1-A expression at preeclampsia mice models. Subjects and Method: Experimental study with parallel group post-test only design. The study was carried out at the Veterinary Medicine Faculty of Airlangga University. Thirty six preeclampsia mice models were made with intravenous injection 10ng anti-Qa-2 on day 1-4 of pregnancy. They were divided into 2 groups: (1)18 mice without treatment (control) and (2) 18 mice were given L-Arginin 200 mg/kgBW/day on day 7-15 of pregnancy. They were terminated on day 16 then immunohistochemistry examination of HIF-1-A expression was done on the placental samples. The dependent variable was placental Hipoxia Inducible Factor-1-Alpha (HIF-1-A) expression. The independent variables were L-Arginin administration. HIF-1-A expression was measured by H-Score method. The data were analyzed by t-test. Results: The mean of placental HIF-1-A expressions of treatment group was lower (Mean= 7.98; SD=9.35) than control group (Mean=41.95; SD= 32.20), and it was statistically significant (p <0.001). Conclusion: L-Arginin reduces the Placental Hypoxia Inducible Factor Alpha (HIF-1-A) expression on preeclampsia mice model. Keywords: L-Arginine, HIF-1-A, Preeclampsia Correspondence: Nutria Widya Purna Anggraini. Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Sebelas Maret/ Dr. Moewardi General Hospital Surakarta. Jl Kolonel Sutarto 132, Surakarta, Central Java, Indonesia. Email: nutria_dr@staff.uns.ac.id. Mobile: 08122651819. Indonesian Journal of Medicine (2020), 05(03): 191-199 https://doi.org/10.26911/theijmed.2020.05.03.03

Effects of quercetin and kaempferol (Main Compound of Moringa oleifera leaves) improve IUGR through decreased hypoxia

Preeclampsia (PE) is special multisystem disorder that due deficient spiral artery remodeling and placental hypoxia with main symptom is hypertension and proteinuria. Deficient spiral artery remodeling can reduce blood flow from maternal to the fetus, therefore occur intrauterine growth restriction and low birth weight babies. Moringa oleifera leaves (MOL) are rich of nutrients, also can be used for medicine. The aim of this study is to evaluate effect of main compounds of ethanol extract MOL to improve IUGR by evaluate rat pups weight and predict the interaction of the main compound of MOL namely Quercetin and Kaempferol on hypoxia and angiogenesis as an approach to prevent preeclampsia. The methods of this research was experimental post-test only control group design and web based: PubChem was used to identify the compound structure and format data SMILE, Swiss target prediction for proteins target prediction, PASS SERVER to predict biological activity of the compounds, while STITCH was used to predict the interaction of compounds with protein target. The result showed that ethanol extract of MOL with the main compound quercetin and kaempferol improve IUGR that shown by increase rat pups weight in administered ethanol extract of MOL group compared to preeclampsia group, MOL extract have the same effect to prevent decrease rat pups weight. In predict main compounds MOL, both of compounds have good biological activity (pa>0.7), target protein prediction = 0.9 to maintain the function of endothelial blood vessel and inhibit hypoxia. Both of compounds work synergistically on hypoxia and angiogenesis through activation and inhibition of HIF-1A.

Morphofunctional peculiarities of placenta infected with streptococcus agalactiae

Objective: To study morphofunctional peculiarities of S. agalactiae-infected placenta. 32 placentas from preterm birth were examined. Morphometric assessment of terminal villi was made with Carl Zeiss microscope using AxioVision software. DNA of intrauterine pathogens was analyzed by a PCR method using domestic test systems. S. agalactiae was found in 9,4 % of the placentas examined. S. agalactiae-infected placentas from preterm birth showed evidence of inflammation and infection processes in membranes, placenta and umbilical cord, signs of chronic placental failure. Morphometric study showed reduced cross-sectional area and perimeter as compared to the mean parameters of infected or non-infected placentas. The specific vascularization features of S.agalactiae-infected placenta are indicative of decreased gas exchange, emergent placental hypoxia and pathogen involvement in the pathogenesis of preterm birth.