Fatty acids, inflammation and angiogenesis in women with gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a metabolic disorder in pregnancy whose prevalence is on the rise. Reports suggest a likely association between inflammation and maternal GDM. A balance between pro and anti-inflammatory cytokines is necessary for the regulation of maternal inflammation system throughout pregnancy. Along with various inflammatory markers, fatty acids also act as pro-inflammatory molecules. However, studies reporting the role of inflammatory markers in GDM are contradictory, suggesting the need of more studies to better understand the role of inflammation in pregnancies complicated by GDM. Inflammatory response can be regulated by angiopoietins suggesting a link between inflammation and angiogenesis. Placental angiogenesis is a normal physiological process which is tightly regulated during pregnancy. Various pro and anti-angiogenic factors influence the regulation of the feto-placental vascular development. Studies evaluating the levels of angiogenic markers in women with GDM are limited and the findings are inconsistent. This review summarizes the available literature on fatty acids, inflammatory markers and angiogenesis in women with GDM. We also discuss the possible link between them and their influence on placental development in GDM.

Assisted reproductive technology (ART) and epigenetic modifications in the placenta.

Assisted reproductive technology (ART) has become common amongst couples with infertility issues. ART is known to be successful, but epidemiological data indicates that ART is associated with placental disorders. Additionally, reports show increased risks of short- and long-term complications in children born to mothers undergoing ART. However, the mechanisms responsible for these events are obscure. The placenta is considered as a key organ for programming of diseases and ART procedures are suggested to alter the placental function and intrauterine growth trajectories. Epigenetic changes in maternal and foetal tissues are suggested to be the underlying mechanisms for these outcomes. Epigenetic regulation is known to evolve following fertilisation and before implantation and subsequently across gestation. During these critical periods of epigenetic 'programming', DNA methylation and chromatin remodelling influence the placental structure and function by regulating the expression of various genes. ART treatment coinciding with epigenetic 'programming' events during gametogenesis and early embryo development may alter the programming phases leading to long-term consequences. Thus, disruptions in placental development observed in ART pregnancies could be associated with altered epigenetic regulation of vital genes in the placenta. The review summarises available literature on the influence of ART procedures on epigenetic changes in the placenta.

Role of Placental Glucose Transporters in Determining Fetal Growth.

Maternal nutrient availability and its transport through the placenta are crucial for fetal development. Nutrients are transported to the fetus via specific transporters present on the microvillous (MVM) and basal membrane (BM) of the placenta. Glucose is the most abundant nutrient transferred to the fetus and plays a key role in the fetal growth and development. The transfer of glucose across the human placenta is directly proportional to maternal glucose concentrations, and is mediated by glucose transporter family proteins (GLUTs). Maternal glucose concentration influences expression and activity of GLUTs in the MVM (glucose uptake) and BM (glucose delivery). Alteration in the number and function of these transporters may affect the growth and body composition of the fetus. The thin-fat phenotype of the Indian baby (low ponderal index, high adiposity) is proposed as a harbinger of future metabolic risk. We propose that placental function mediated through nutrient transporters contributes to the phenotype of the baby, specifically that glucose transporters will influence neonatal fat. This review discusses the role of various glucose transporters in the placenta in determining fetal growth and body composition, in light of the above hypothesis.

Unravelling the potential of angiogenic factors for the early prediction of preeclampsia.

Preeclampsia is a multisystem, multiorgan hypertensive disorder of pregnancy responsible for maternal and perinatal morbidity and mortality in low- and middle-income countries. The classic diagnostic features hold less specificity for preeclampsia and its associated adverse outcomes, suggesting a need for specific and reliable biomarkers for the early prediction of preeclampsia. The imbalance of pro- and antiangiogenic circulatory factors contributes to the pathophysiology of preeclampsia. Several studies have examined the profile of angiogenic factors in preeclampsia to search for a biomarker that will improve the diagnostic ability of preeclampsia and associated adverse outcomes. This may help in more efficient patient management and the reduction of associated health care costs. This article reviews the findings from previous studies published to date on angiogenic factors and suggests a need to apply a multivariable model from the beginning of pregnancy and continuing throughout gestation for the early and specific prediction of preeclampsia.

Peroxisome Proliferator-Activated Receptors (PPAR), fatty acids and microRNAs: Implications in women delivering low birth weight babies.

Low birth weight (LBW) babies are associated with neonatal morbidity and mortality and are at increased risk for noncommunicable diseases (NCDs) in later life. However, the molecular determinants of LBW are not well understood. Placental insufficiency/dysfunction is the most frequent etiology for fetal growth restriction resulting in LBW and placental epigenetic processes are suggested to be important regulators of pregnancy outcome. Early life exposures like altered maternal nutrition may have long-lasting effects on the health of the offspring via epigenetic mechanisms like DNA methylation and microRNA (miRNA) regulation. miRNAs have been recognized as major regulators of gene expression and are known to play an important role in placental development. Angiogenesis in the placenta is known to be regulated by transcription factor peroxisome proliferator-activated receptor (PPAR) which is activated by ligands such as long-chain-polyunsaturated fatty acids (LCPUFA). In vitro studies in different cell types indicate that fatty acids can influence epigenetic mechanisms like miRNA regulation. We hypothesize that maternal fatty acid status may influence the miRNA regulation of PPAR genes in the placenta in women delivering LBW babies. This review provides an overview of miRNAs and their regulation of PPAR gene in the placenta of women delivering LBW babies.Abbreviations: AA - Arachidonic Acid; Ago2 - Argonaute2; ALA - Alpha-Linolenic Acid; ANGPTL4 - Angiopoietin-Like Protein 4; C14MC - Chromosome 14 miRNA Cluster; C19MC - Chromosome 19 miRNA Cluster; CLA - Conjugated Linoleic Acid; CSE - Cystathionine γ-Lyase; DHA - Docosahexaenoic Acid; EFA - Essential Fatty Acids; E2F3 - E2F transcription factor 3; EPA - Eicosapentaenoic Acid; FGFR1 - Fibroblast Growth Factor Receptor 1; GDM - Gestational Diabetes Mellitus; hADMSCs - Human Adipose Tissue-Derived Mesenchymal Stem Cells; hBMSCs - Human Bone Marrow Mesenchymal Stem Cells; HBV - Hepatitis B Virus; HCC - Hepatocellular Carcinoma; HCPT - Hydroxycamptothecin; HFD - High-Fat Diet; Hmads - Human Multipotent Adipose-Derived Stem; HSCS - Human Hepatic Stellate Cells; IUGR - Intrauterine Growth Restriction; LA - Linoleic Acid; LBW - Low Birth Weight; LCPUFA - Long-Chain Polyunsaturated Fatty Acids; MEK1 - Mitogen-Activated Protein Kinase 1; MiRNA - MicroRNA; mTOR - Mammalian Target of Rapamycin; NCDs - NonCommunicable Diseases; OA - Oleic Acid; PASMC - Pulmonary Artery Smooth Muscle Cell; PLAG1 - Pleiomorphic Adenoma Gene 1; PPAR - Peroxisome Proliferator-Activated Receptor; PPARα - PPAR alpha; PPARγ - PPAR gamma; PPARδ - PPAR delta; pre-miRNA - precursor miRNA; RISC - RNA-Induced Silencing Complex; ROS - Reactive Oxygen Species; SAT - Subcutaneous Adipose Tissue; WHO - World Health Organization.

Protocol for a cluster randomised trial evaluating a multifaceted intervention starting preconceptionally-Early Interventions to Support Trajectories for Healthy Life in India (EINSTEIN): a Healthy Life Trajectories Initiative (HeLTI) Study.

INTRODUCTION: The Healthy Life Trajectories Initiative is an international consortium comprising four harmonised but independently powered trials to evaluate whether an integrated intervention starting preconceptionally will reduce non-communicable disease risk in their children. This paper describes the protocol of the India study. METHODS AND ANALYSIS: The study set in rural Mysore will recruit ~6000 married women over the age of 18 years. The village-based cluster randomised design has three arms (preconception, pregnancy and control; 35 villages per arm). The longitudinal multifaceted intervention package will be delivered by community health workers and comprise: (1) measures to optimise nutrition; (2) a group parenting programme integrated with cognitive-behavioral therapy; (3) a lifestyle behaviour change intervention to support women to achieve a diverse diet, exclusive breast feeding for the first 6 months, timely introduction of diverse and nutritious infant weaning foods, and adopt appropriate hygiene measures; and (4) the reduction of environmental pollution focusing on indoor air pollution and toxin avoidance.The primary outcome is adiposity in children at age 5 years, measured by fat mass index. We will report on a host of intermediate and process outcomes. We will collect a range of biospecimens including blood, urine, stool and saliva from the mothers, as well as umbilical cord blood, placenta and specimens from the offspring.An intention-to-treat analysis will be adopted to assess the effect of interventions on outcomes. We will also undertake process and economic evaluations to determine scalability and public health translation. ETHICS AND DISSEMINATION: The study has been approved by the institutional ethics committee of the lead institute. Findings will be published in peer-reviewed journals. We will interact with policy makers at local, national and international agencies to enable translation. We will also share the findings with the participants and local community through community meetings, newsletters and local radio. TRIAL REGISTRATION NUMBER: ISRCTN20161479, CTRI/2020/12/030134; Pre-results.

Placental growth factor and Fms related tyrosine kinase-1 are hypomethylated in preeclampsia placentae.

Aim: This study aims to examine the DNA methylation (DNAm) and expression patterns of genes associated with placental angiogenesis in preeclampsia. Materials & methods: DNAm and expression were examined in normotensive (n = 100) and preeclampsia (n = 100) women using pyrosequencing and quantitative real-time PCR respectively. Results: Hypomethylation at several CpGs was observed in PlGF and FLT-1 in women with preeclampsia compared to normotensive controls. PlGF expression was lower in women with preeclampsia while FLT-1 expression was comparable. DNAm at various CpGs was negatively correlated with expression in both the genes and were associated with maternal blood pressure and birth outcomes. Conclusion: DNAm and expression of angiogenic factors in placentae are differentially regulated in preeclampsia and influence birth outcomes.

Role of maternal nutrition and oxidative stress in placental telomere attrition in women with preeclampsia.

Background:Maternal nutrition influences the growth and development of the fetus and influences pregnancy outcome. We have earlier demonstrated altered maternal nutrition and increased oxidative stress in women with preeclampsia. Oxidative stress is known to be associated with reduced telomere length and short telomere aggregates. Increased telomere attrition leads to increased cellular senescence and tissue ageing. Methods:The present review focuses on the role of maternal nutrition and oxidative stress in telomere attrition in preeclampsia. Results and Conclusion:Future studies need to examine the association between maternal nutritional status in early pregnancy, oxidative stress and telomere attrition in preeclampsia.

Maternal vitamin D deficiency influences long-chain polyunsaturated fatty acids and pregnancy outcome in association with alterations in one-carbon metabolism.

Preeclampsia is a pregnancy-specific disorder, leading to maternal and infant morbidity and mortality. Abnormal placentation has been reported in preeclampsia. Nutrients like vitamin D and long-chain polyunsaturated fatty acids (LCPUFA) are known to play a role in placental development. In an animal model, we have previously demonstrated that maternal vitamin D deficiency increases the thromboxane/prostacyclin ratio and contributes to inflammation and vasoconstriction. We hypothesize that maternal vitamin D status influences placental LCPUFA metabolism through alterations in one carbon metabolism in women with preeclampsia. To test this hypothesis, we recruited 69 normotensive control (NC) women and 50 women with preeclampsia. Women with preeclampsia had lower placental protein and mRNA levels of cystathionine-ß-synthase (CBS), higher plasma malondialdehyde (MDA) levels and higher levels of arachidonic acid (AA) and total omega-6 fatty acids in the placenta. Women with preeclampsia also demonstrated higher placental mRNA levels of cyclooxygenase-2 (COX-2) as compared to NC women. Maternal 25(OH)D levels were negatively associated with maternal plasma MDA levels. Placental vitamin D receptor (VDR) levels were positively associated with CBS while maternal MDA levels were positively associated with serum levels of thromboxane-B2 (TXB2) levels. Our findings indicate that vitamin D deficiency increases oxidative stress through alterations in one carbon metabolism to influence pro-inflammatory omega-6 metabolic pathway in the placenta. This study demonstrates a possible mechanism through which vitamin D deficiency can result in an imbalance in the LCPUFA metabolites and contribute to placental inflammation and endothelial dysfunction in preeclampsia.

Placental lipid metabolism in preeclampsia.

OBJECTIVES: The current study examines the placental and maternal lipid profile and expression of genes involved in placental lipid metabolism in women with preeclampsia. METHODS: The current study includes normotensive control women (n = 40) and women with preeclampsia (n = 39). Preeclampsia women were further classified into women delivering at term preeclampsia (T-PE; n = 15) and preterm preeclampsia (PT-PE; n = 24). RESULTS: There were no significant differences in maternal lipid profile between the T-PE and normotensive control groups. Maternal plasma VLDL (P < 0.05) and ratios of total cholesterol : HDL (P < 0.05), atherogenic index [log (triglycerides/HDL)] (P < 0.01) and apolipoprotein B : apolipoprotein A (P < 0.05) were higher in the PT-PE group as compared with the normotensive control group. Placental total cholesterol and HDL levels were higher (P < 0.05) in the T-PE as compared with the normotensive control group. Higher placental triglycerides (P < 0.05) were observed in PT-PE group compared with T-PE group. Placental mRNA levels of peroxisome proliferator activated receptor α, carnitine palmitoyl transferase-1, cluster of differentiation 36 and lipoprotein lipases were lower (P < 0.05) in the PT-PE than normotensive control group. A negative association of mRNA levels of peroxisome proliferator activated receptor α (r = -0.246, P = 0.032; r = -0.308, P = 0.007, respectively), carnitine palmitoyl transferase-1 (r = -0.292, P = 0.011; r = -0.366, P = 0.001), lipoprotein lipases (r = -0.296, P = 0.010; r = -0.254, P = 0.028) with SBP and DBP was observed. There was a positive association of placental triglycerides (r = 0.244, P = 0.031) with DBP. CONCLUSION: Women with preeclampsia exhibit higher lipid : lipoprotein ratios suggesting an atherogenic state particularly in women delivering preterm. Lower expression of genes involved in placental fatty acid oxidation and transport was also observed in preeclampsia.

Exploring the role of LC-PUFA metabolism in pregnancy complications.

Maternal nutrition during pregnancy plays a significant role in growth and development of the placenta and influencing pregnancy outcome. Suboptimal nutritional status during early gestational period compromises the normal course of pregnancy leading to adverse maternal and fetal outcomes. Omega-3 and omega-6 long chain polyunsaturated fatty acids (LC-PUFA) are important for the growth and development of the placenta. Maternal fatty acids and their metabolites influence the normal course of pregnancy by regulating cell growth and development, cell signaling, regulate angiogenesis, modulate inflammatory responses and influence various structural and functional processes. Alterations in LC-PUFA and their metabolites may result in inadequate spiral artery remodeling or placental angiogenesis leading to structural and functional deficiency of the placenta which contributes to several pregnancy complications like preeclampsia, gestational diabetes mellitus, intrauterine growth restriction, and results in adverse birth outcomes. In this review, we summarize studies examining the role of fatty acids and their metabolites in pregnancy. We also discuss the possible molecular mechanisms through which LC-PUFA influences placental growth and development. Studies have demonstrated that omega-3 fatty acid supplementation lowers the incidence of preterm births, but its effect on reducing pregnancy complications are inconclusive.

Differential Expression of Nerve Growth Factor (NGF) and Brain Derived Neurotrophic Factor (BDNF) in Different Regions of Normal and Preeclampsia Placentae.

Background: Our recent study indicates differential protein levels of neurotrophins and angiogenic factors in various regions of the normotensive and preeclampsia (PE) placenta. These changes may be in a response to differential mRNA expression of neurotrophins.Methods: This study examines the mRNA levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in different regions of the placenta in normotensive control (NC) women and women with PE. Thirty NC women and forty one women with PE (18 delivered at term [T-PE] and 23 delivered preterm [PT-PE]) were included in the study. Placental samples were taken from four regions: central basal (CM), central chorionic (CF), peripheral basal (PM), and peripheral chorionic (PF). The mRNA levels of neurotrophins were measured by quantitative real-time PCR.Results: The BDNF mRNA levels were higher in peripheral fetal region as compared to peripheral basal region in NC (p < 0.05) group, PE group (p < 0.05) and term PE group (p < 0.01). The BDNF mRNA levels were lower in the central basal region of preterm PE group (p < 0.05) as compared to the NC group.Conclusion: The present study indicates that NGF and BDNF are expressed differentially across various regions of the placenta. This has implications for selection of the sampling site in the placenta while carrying out placental studies.

The REVAMP study: research exploring various aspects and mechanisms in preeclampsia: study protocol.

BACKGROUND: Preeclampsia is a major cause of maternal, fetal and neonatal morbidity and mortality, particularly in developing countries. Considering the burden of preeclampsia and its associated complications, it is important to understand the underlying risk factors and mechanisms involved in its etiology. There is considerable interest in the potential for dietary long chain polyunsaturated fatty acids (LCPUFA) as a therapeutic intervention to prevent preeclampsia, as they are involved in angiogenesis, oxidative stress, and inflammatory pathways. METHODS: The REVAMP study (Research Exploring Various Aspects and Mechanisms in Preeclampsia) follows a cohort of pregnant women from early pregnancy until delivery to examine longitudinally the associations of maternal LCPUFA with clinical outcome in preeclampsia. A multisite centre for advanced research was established and pregnant women coming to Bharati hospital and Gupte hospital, Pune, India for their first antenatal visit are recruited and followed up at 11-14 weeks, 18-22 weeks, 26-28 weeks, and at delivery. Their personal, obstetric, clinical, and family history are recorded. Anthropometric measures (height, weight), food frequency questionnaire (FFQ), physical activity, socioeconomic status, fetal ultrasonography, and color Doppler measures are recorded at different time points across gestation. Maternal blood at all time points, cord blood, and placenta at delivery are collected, processed and stored at - 80 °C. The children's anthropometry is assessed serially up to the age of 2 years, when their neurodevelopmental scores will be assessed. DISCUSSION: This study will help in early identification of pregnant women who are at risk of developing preeclampsia. The prospective design of the study for the first time will establish the role of LCPUFA in understanding the underlying biochemical and molecular mechanisms involved in preeclampsia and their association with developmental programming in children.

Maternal vitamin D deficiency increases the thromboxane/prostacyclin ratio through alterations in the one-carbon cycle in Wistar rats.

This study aims to test the hypothesis that vitamin D deficiency can influence long-chain polyunsaturated fatty acid metabolism through alterations in the one-carbon cycle. Wistar rats (n = 8 per group) were given either a control (1,000 IU D3/kg diet) or a vitamin D deficient (VDD) (0 IU D3/kg diet) diet from pre-pregnancy to delivery. On day 20 of gestation, pregnant female rats were delivered by C-section to collect placenta and blood. VDD group demonstrated high serum parathyroid hormone, low serum phosphate, low plasma folate, higher plasma homocysteine, and higher plasma malondialdehyde levels (P < 0.05 for all) as compared to control. Lower protein levels of placental cystathionine-ß-synthase enzyme (P < 0.05) were observed in the VDD group as compared to control. VDD group demonstrated higher placental mRNA levels of the enzymes phospholipase A2 and cyclooxygenase-2 (P < 0.05 for both) as compared to control. Protein levels of the enzymes phospholipase A2 and cyclooxygenase-2 were lower (P < 0.05 for both) in the VDD group as compared to the control group. The ratio of thromboxane B2 and 6-keto prostaglandin F1α in serum was higher (P < 0.05) in the VDD group as compared to control; although the serum levels of 6-keto prostaglandin F1α and thromboxane B2 were similar in both the groups. Our findings suggest that increased oxidative stress due to maternal vitamin D deficiency results in the imbalance between the vasoconstrictor (thromboxane B2 ) and vasodilator (6-keto prostaglandin F1α ) eicosanoids, which may lead to endothelial dysfunction and poor pregnancy outcome. © 2019 BioFactors, 45 (4):548-555, 2019.

Effect of a daily snack containing green leafy vegetables on women's fatty acid status: a randomized controlled trial in Mumbai, India.

BACKGROUND AND OBJECTIVES: There are few data on the fatty acid status of non-pregnant Indian women. Our objective was to investigate the effect of a snack containing green leafy vegetables (GLVs) on women's erythrocyte long chain polyunsaturated fatty acid status (LCPUFA). METHODS AND STUDY DESIGN: Non-pregnant women (n=222) aged 14-35 years from Mumbai slums were randomized to consume a snack containing GLVs, fruit and milk (treatment) or a control snack containing foods of low micronutrient content such as potato and onion, daily under observation. One treatment snack contained a mean (SD) of 54.1 (33.7) mg alpha-linolenic acid (ALA) and one control snack contained 4.1 (3.4) mg ALA. Blood was collected at baseline (0 weeks) and after 12 weeks of supplementation. Erythrocyte fatty acids were analyzed using gas chromatography and expressed as g/100g fatty acids. Plasma malondialdehyde, homocysteine, and erythrocyte superoxide dismutase and glutathione peroxidase were measured. The effect of the treatment on 12 week LCPUFA was assessed using ANCOVA models. RESULTS: Median (IQR) erythrocyte DHA in the treatment group increased from 1.50 (1.11, 2.03) at baseline to 1.86 (1.50, 2.43) (p<0.001) at 12 weeks, and fell in controls from 1.78 (1.37, 2.32) to 1.60 (1.32, 2.04) (p<0.001). The total n-3 fatty acids increased in the treatment group. There was no effect on malondialdehyde and antioxidant enzyme levels. Plasma homocysteine at 0 and 12 weeks was inversely associated with erythrocyte DHA at 12 weeks. CONCLUSION: Daily consumption of a snack containing GLV improved women's erythrocyte DHA levels without increasing oxidative stress.

Maternal one carbon metabolism through increased oxidative stress and disturbed angiogenesis can influence placental apoptosis in preeclampsia.

Adequate maternal nutrition is critical for a healthy pregnancy outcome and poor maternal nutrition is known to be associated with pregnancy complications like preeclampsia. We have earlier demonstrated that there is an imbalance in the levels of micronutrients (folate and vitamin B12) along with low levels of long chain polyunsaturated fatty acids (LCPUFA) and high homocysteine levels in women with preeclampsia. Homocysteine is known to be involved in the formation of free radicals leading to increased oxidative stress. Higher oxidative stress has been shown to be associated with increased apoptotic markers in the placenta. Preeclampsia is of placental origin and is associated with increased oxidative stress, disturbed angiogenesis and placental apoptosis. The process of angiogenesis is important for placental and fetal development and various angiogenic growth factors inhibit apoptosis by inactivation of proapoptotic proteins through a series of cellular signalling pathways. We propose that an altered one carbon cycle resulting in increased oxidative stress and impaired angiogenesis will contribute to increased placental apoptosis leading to preeclampsia. Understanding the association of one carbon cycle components and the possible mechanisms through which they regulate apoptosis will provide clues for reducing risk of pregnancy complications.

Matrix metalloproteinases-2 (MMP-2) and matrix metalloproteinases -9 (MMP-9) are differentially expressed in different regions of normal and preeclampsia placentae.

Matrix metalloproteinases (MMPs) are involved in the extracellular matrix (ECM) remodeling during human placentation and parturition and have been shown to be associated with oxidative stress. Placental regional changes in oxygen availability and oxidative stress indices may influence regional differences in expression of MMPs. This study examines the protein and mRNA levels of MMP-2 and MMP-9 in different regions of the placenta in normotensive control (NC) women and women with preeclampsia (PE). Fifty-two NC women and 43 women with PE (18 delivered at term [T-PE] and 25 delivered preterm [PT-PE]) were recruited. Placental samples were taken from four regions: central basal (CM), central chorionic (CF), peripheral basal (PM), and peripheral chorionic (PF). MMP protein and mRNA levels were measured by ELISA and quantitative real time PCR, respectively. MMP-2 protein levels were higher in all the placental regions (P < 0.05) from PT-PE group as compared to the respective regions from the NC and T-PE groups. MMP-9 mRNA levels were higher in CM region as compared to CF and PM regions (P < 0.05) in the NC group and compared to CF and PF regions (P < 0.05) in the T-PE group. The MMP-9 mRNA levels were lower in the CF region in the PT-PE and T-PE groups (P < 0.05) as compared to the NC group. Elevated levels of MMP-2 protein levels were observed in all regions of PT-PE placenta possibly influencing the degradation of placental ECM. Lower mRNA expression of MMP-9 both in PT-PE and T-PE may contribute to a disturbed placental vascularization.

VEGF and VEGFR1 levels in different regions of the normal and preeclampsia placentae.

Altered placental angiogenesis is implicated in the pathophysiology of preeclampsia. We have earlier reported placental regional differences in oxidative stress markers and neurotrophins. Oxidative stress and neurotrophins are reported to regulate angiogenesis. This study aims to examine protein and mRNA levels of vascular endothelial growth factor (VEGF) and VEGF receptor 1 (VEGFR1) in four regions [central maternal (CM), central fetal (CF), peripheral maternal (PM), and peripheral fetal (PF)] of the placenta in normotensive control (NC) women (n = 51) and women with preeclampsia (PE) (n = 43) [18 delivered at term (T-PE) and 25 delivered preterm (PT-PE)]. In all groups, CF region reported highest VEGF protein levels compared to all other regions. VEGF mRNA level was higher in CF region as compared to CM region in PE group (p < 0.05). VEGF levels were lower in all regions of PE, T-PE, and PT-PE groups (p < 0.05) as compared to their respective regions in NC group. VEGFR1 levels were lower in CF (p < 0.05) and PF (p < 0.01) regions as compared to CM region only in control. However, VEGFR1 levels were higher in CF (p < 0.05) and PF (p < 0.01) regions of PT-PE group as compared to control. VEGFR1 mRNA level was higher in PM region of PE group and T-PE group (p < 0.05 for both) as compared to control. VEGF levels in the PF region were positively associated with birth weight and placental weight. This study describes placental regional changes in angiogenic factors particularly highlighting increased VEGF in CF region possibly in response to hypoxic conditions prevailing in placenta.

Differential accumulation of vimentin fragments in preeclamptic placenta.

Preeclampsia is a pregnancy complication that is the result of abnormal placentation because of inadequate trophoblast invasion into spiral arteries that prevent normal blood flow to the placenta. We report the alteration in vimentin protein proteolysis in placenta of normotensive and preeclamptic women, which is known to have a role in many physiological functions other than its major function in the structural integrity of the cell. Placental proteome from normotensive (n = 25) and preeclamptic pregnancies (n = 25) showed eight differentially accumulated protein spots of vimentin (proteolytic fragments) by two-dimensional electrophoresis. Immunoblots of normotensive and preeclamptic placenta revealed a difference in proteolytic processing of vimentin. In particular, lower molecular weight vimentin fragments of 32 and 20 kDa were 3.3 and 2.6-fold (p < 0.0001) higher, respectively, in preeclampsia compared with normotensive placenta.

Hypermethylated CpG sites in the MTR gene promoter in preterm placenta.

AIM: Altered maternal one-carbon metabolism influences placental DNA methylation patterns and 'programs' the fetus for noncommunicable diseases in adult life. EXPERIMENTAL PROCEDURES: Levels of plasma folate, vitamin B12, homocysteine, mRNA and protein levels of MTHFR and MTR enzymes in placenta were compared among women delivering preterm (n = 83) and term (n = 75). MTR promoter CpG methylation was undertaken. RESULTS: MTHFR and MTR mRNA levels were higher while protein levels were lower, and MTR CpG sites were hypermethylated in the preterm group, as compared with the term group. Methylated CpG sites were negatively associated with maternal plasma vitamin B12 levels. CONCLUSION: Study suggests a dysregulation of enzyme genes in remethylation arm of the one-carbon metabolism in placenta of women delivering preterm.