Epigenetic processes during preeclampsia and effects on fetal development and chronic health

2021 ◽  
Vol 135 (19) ◽  
pp. 2307-2327
Author(s):  
Usman M. Ashraf ◽  
Dalton L. Hall ◽  
Adam Z. Rawls ◽  
Barbara T. Alexander
Keyword(s):  
Fetal Growth ◽  
Trophoblast Invasion ◽  
Placental Development ◽  
Regulatory Processes ◽  
Effective Interventions ◽  
Downstream Effects ◽  
Increased Risk ◽  
Exact Etiology ◽  
Cv Disease ◽  
Epigenetic Processes

Abstract Preeclampsia (PE), the leading cause of maternal and fetal morbidity and mortality, is associated with poor fetal growth, intrauterine growth restriction (IUGR) and low birth weight (LBW). Offspring of women who had PE are at increased risk for cardiovascular (CV) disease later in life. However, the exact etiology of PE is unknown. Moreover, there are no effective interventions to treat PE or alleviate IUGR and the developmental origins of chronic disease in the offspring. The placenta is critical to fetal growth and development. Epigenetic regulatory processes such as histone modifications, microRNAs and DNA methylation play an important role in placental development including contributions to the regulation of trophoblast invasion and remodeling of the spiral arteries. Epigenetic processes that lead to changes in placental gene expression in PE mediate downstream effects that contribute to the development of placenta dysfunction, a critical mediator in the onset of PE, impaired fetal growth and IUGR. Therefore, this review will focus on epigenetic processes that contribute to the pathogenesis of PE and IUGR. Understanding the epigenetic mechanisms that contribute to normal placental development and the initiating events in PE may lead to novel therapeutic targets in PE that improve fetal growth and mitigate increased CV risk in the offspring.

scholarly journals Levels of miR-374 increase in BeWo b30 cells exposed to hypoxia

2021 ◽  
Author(s):  
EN Knyazev ◽  
SYu Paul
Keyword(s):  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Target Genes ◽  
Expression Profiles ◽  
Growth Restriction ◽  
Trophoblast Invasion ◽  
Placental Development ◽  
Cell Potential ◽  
Bewo B30 ◽  
Next Generation Sequencing Ngs

In humans, trophoblast hypoxia during placental development can be a cause of serious pregnancy complications, such as preeclampsia and fetal growth restriction. The pathogenesis of these conditions is not fully clear and may be associated with changed expression of some genes and regulatory molecules, including miRNA, in trophoblast cells. The aim of this study was to analyze miRNA profiles and measure the expression of their target genes in a model of trophoblast hypoxia. Human choriocarcinoma BeWo b30 cells were used as a trophoblast model. Hypoxia was induced by cobalt chloride (CoCl2) and an oxyquinoline derivative. MRNA and miRNA expression profiles were evaluated by means of next generation sequencing (NGS); the expression of individual genes was analyzed by PCR. We studied the secondary structure of mRNAs of target genes for those miRNAs whose expression had changed significantly and analyzed potential competition between these miRNAs for the binding site. The observed changes in the expression of the key genes involved in the response to hypoxia confirmed the feasibility of using CoCl2 and the oxyquinoline derivative as hypoxia inducers. The analysis revealed an increase in miR-374 levels following the activation of the hypoxia pathway in our trophoblast model. The changes were accompanied by a reduction in FOXM1 mRNA expression; this mRNA is a target for hsa-miR-374a-5p and hsa-miR374b-5p, which can compete with hsa-miR-21-5p for the binding sites on FOXM1 mRNA. The involvement of FOXM1 in the regulation of the invasive cell potential suggests the role of miR-374 and FOXM1 in the pathogenesis of disrupted trophoblast invasion during placental development as predisposing for fetal growth restriction and preeclampsia.

scholarly journals The Role of Placental Homeobox Genes in Human Fetal Growth Restriction

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Padma Murthi ◽  
Gayathri Rajaraman ◽  
Shaun Patrick Brennecke ◽  
Bill Kalionis
Keyword(s):  
Pregnancy Outcome ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Adverse Pregnancy Outcome ◽  
Growth Restriction ◽  
Placental Development ◽  
Increased Risk ◽  
Adverse Pregnancy

Fetal growth restriction (FGR) is an adverse pregnancy outcome associated with significant perinatal and paediatric morbidity and mortality, and an increased risk of chronic disease later in adult life. One of the key causes of adverse pregnancy outcome is fetal growth restriction (FGR). While a number of maternal, fetal, and environmental factors are known causes of FGR, the majority of FGR cases remain idiopathic. These idiopathic FGR pregnancies are frequently associated with placental insufficiency, possibly as a result of placental maldevelopment. Understanding the molecular mechanisms of abnormal placental development in idiopathic FGR is, therefore, of increasing importance. Here, we review our understanding of transcriptional control of normal placental development and abnormal placental development associated with human idiopathic FGR. We also assess the potential for understanding transcriptional control as a means for revealing new molecular targets for the detection, diagnosis, and clinical management of idiopathic FGR.

scholarly journals Nutrient sensor signaling pathways and cellular stress in fetal growth restriction

2019 ◽  
Vol 62 (2) ◽  
pp. R155-R165 ◽  
Author(s):  
Bethany Hart ◽  
Elizabeth Morgan ◽  
Emilyn U Alejandro
Keyword(s):  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Cellular Stress ◽  
Nutrient Sensing ◽  
Growth Restriction ◽  
Trophoblast Invasion ◽  
Supporting Evidence ◽  
Placental Development ◽  
Nutrient Regulation ◽  
Placental Perfusion

Fetal growth restriction is one of the most common obstetrical complications resulting in significant perinatal morbidity and mortality. The most frequent etiology of human singleton fetal growth restriction is placental insufficiency, which occurs secondary to reduced utero-placental perfusion, abnormal placentation, impaired trophoblast invasion and spiral artery remodeling, resulting in altered nutrient and oxygen transport. Two nutrient-sensing proteins involved in placental development and glucose and amino acid transport are mechanistic target of rapamycin (mTOR) and O-linked N-acetylglucosamine transferase (OGT), which are both regulated by availability of oxygen. Impairment in either of these pathways is associated with fetal growth restriction and accompanied by cellular stress in the forms of hypoxia, oxidative and endoplasmic reticulum (ER) stress, metabolic dysfunction and nutrient starvation in the placenta. Recent evidence has emerged regarding the potential impact of nutrient sensors on fetal stress response, which occurs in a sexual dysmorphic manner, indicating a potential element of genetic gender susceptibility to fetal growth restriction. In this mini review, we focus on the known role of mTOR and OGT in placental development, nutrient regulation and response to cellular stress in human fetal growth restriction with supporting evidence from rodent models.

scholarly journals Combinations of Maternal KIR and Fetal HLA-C Genes Influence the Risk of Preeclampsia and Reproductive Success

2004 ◽  
Vol 200 (8) ◽  
pp. 957-965 ◽  
Author(s):  
Susan E. Hiby ◽  
James J. Walker ◽  
Kevin M. O'Shaughnessy ◽  
Christopher W.G. Redman ◽  
Mary Carrington ◽  
...  
Keyword(s):  
Reproductive Success ◽  
Physiological Role ◽  
Reciprocal Relationship ◽  
Trophoblast Invasion ◽  
Human Populations ◽  
Placental Development ◽  
Increased Risk ◽  
Key Factor ◽  
Missing Self ◽  
Risk Of Preeclampsia

Preeclampsia is a serious complication of pregnancy in which the fetus receives an inadequate supply of blood due to failure of trophoblast invasion. There is evidence that the condition has an immunological basis. The only known polymorphic histocompatibility antigens on the fetal trophoblast are HLA-C molecules. We tested the idea that recognition of these molecules by killer immunoglobulin receptors (KIRs) on maternal decidual NK cells is a key factor in the development of preeclampsia. Striking differences were observed when these polymorphic ligand: receptor pairs were considered in combination. Mothers lacking most or all activating KIR (AA genotype) when the fetus possessed HLA-C belonging to the HLA-C2 group were at a greatly increased risk of preeclampsia. This was true even if the mother herself also had HLA-C2, indicating that neither nonself nor missing-self discrimination was operative. Thus, this interaction between maternal KIR and trophoblast appears not to have an immune function, but instead plays a physiological role related to placental development. Different human populations have a reciprocal relationship between AA frequency and HLA-C2 frequency, suggesting selection against this combination. In light of our findings, reproductive success may have been a factor in the evolution and maintenance of human HLA-C and KIR polymorphisms.

Long-term effects of nutritional programming of the embryo and fetus: mechanisms and critical windows

2007 ◽  
Vol 19 (1) ◽  
pp. 53 ◽  
Author(s):  
Michael E. Symonds ◽  
Terence Stephenson ◽  
David S. Gardner ◽  
Helen Budge
Keyword(s):  
Fetal Growth ◽  
Epidemiological Studies ◽  
Maternal Plasma ◽  
Metabolic Effects ◽  
Global Changes ◽  
Long Term Effects ◽  
Placental Development ◽  
Increased Risk ◽  
Large Animals

The maternal nutritional and metabolic environment is critical in determining not only reproduction, but also long-term health and viability. In the present review, the effects of maternal nutritional manipulation at defined stages of gestation coinciding with embryogenesis, maximal placental or fetal growth will be discussed. Long-term outcomes from these three developmental windows appear to be very different, with brain and cardiovascular function being most sensitive to influences in the embryonic period, the kidney during placental development and adipose tissue in the fetal phase. In view of the similarities in fetal development, number and maturity at birth, there are close similarities in these outcomes between findings from epidemiological studies in historical human cohorts and nutritional manipulation of large animals, such as sheep. One key nutrient that may modulate the long-term metabolic effects is the supply of glucose from the mother to the fetus, because this is sensitive to both global changes in food intake, maternal glucocorticoid status and an increase in the carbohydrate content of the diet. The extent to which these dietary-induced changes may reflect epigenetic changes remains to be established, especially when considering the very artificial diets used to induce these types of effects. In summary, the maintenance of a balanced and appropriate supply of glucose from the mother to the fetus may be pivotal in ensuring optimal embryonic, placental and fetal growth. Increased or decreased maternal plasma glucose alone, or in conjunction with other macro- or micronutrients, may result in offspring at increased risk of adult diseases.

scholarly journals Characterization of the adverse effects of nicotine on placental development: in vivo and in vitro studies

2014 ◽  
Vol 306 (4) ◽  
pp. E443-E456 ◽  
Author(s):  
A. C. Holloway ◽  
A. Salomon ◽  
M. J. Soares ◽  
V. Garnier ◽  
S. Raha ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Cell Line ◽  
Angiogenic Factor ◽  
Trophoblast Invasion ◽  
Placental Development ◽  
Nicotine Receptors ◽  
Increased Risk ◽  
The Impact

In utero exposure to nicotine is associated with increased risk of numerous adverse fetal and neonatal outcomes, which suggests that it acts directly to affect placental development and the establishment of the fetomaternal circulation (FC). This study used both in vivo [Wistar rats treated with 1 mg/kg nicotine from 2 wk prior to mating until gestational day (GD) 15] and in vitro (RCHO-1 cell line; treated with 10−9 to 10−3M nicotine) models to examine the effects of nicotine on these pathways. At GD 15, control and treated placentas were examined for the impact of nicotine on 1) trophoblast invasion, proliferation, and degree of hypoxia, 2) labyrinth vascularization, 3) expression of key genes of placental development, and 4) expression of placental angiogenic factors. The RCHO-1 cell line was used to determine the direct effects of nicotine on trophoblast differentiation. Our in vivo experiments show that nicotine inhibits trophoblast interstitial invasion, increases placental hypoxia, downregulates labyrinth vascularization as well as key transcription factors Hand1 and GCM1, and decreases local and circulating EG-VEGF, a key placental angiogenic factor. The in vitro experiments confirmed the inhibitory effects of nicotine on the trophoblast migration, invasion, and differentiation processes and demonstrated that those effects are most likely due to a dysregulation in the expression of nicotine receptors and a decrease in MMP9 activity. Taken together, these data suggest that adverse effects of maternal smoking on pregnancy outcome are due in part to direct and endocrine effects of nicotine on the main processes of placental development and establishment of FC.

Cardiovascular Complications of Sleep Disorders: A Better Night’s Sleep for a Healthier Heart / From Bench to Bedside

2020 ◽  
Vol 19 (2) ◽  
pp. 210-232 ◽  
Author(s):  
Theodora A. Manolis ◽  
Antonis A. Manolis ◽  
Evdoxia J. Apostolopoulos ◽  
Helen Melita ◽  
Antonis S. Manolis
Keyword(s):  
Sleep Disorders ◽  
Disease Risk ◽  
Behavioral Therapy ◽  
Benzodiazepine Receptor ◽  
Cardiovascular Complications ◽  
Gamma Aminobutyric Acid ◽  
Acid Type ◽  
Increased Risk ◽  
Cv Disease ◽  
Meta Analyses

: Sleep is essential to and an integral part of life and when lacking or disrupted, a multitude of mental and physical pathologies ensue, including cardiovascular (CV) disease, which increases health care costs. Several prospective studies and meta-analyses show that insomnia, short (<7h) or long (>9h) sleep and other sleep disorders are associated with an increased risk of hypertension, metabolic syndrome, myocardial infarction, heart failure, arrhythmias, CV disease risk and/or mortality. The mechanisms by which insomnia and other sleep disorders lead to increased CV risk may encompass inflammatory, immunological, neuro-autonomic, endocrinological, genetic and microbiome perturbations. Guidelines are emerging that recommend a target of >7 h of sleep for all adults >18 years for optimal CV health. Treatment of sleep disorders includes cognitive-behavioral therapy considered the mainstay of non-pharmacologic management of chronic insomnia, and drug treatment with benzodiazepine receptor agonists binding to gamma aminobutyric acid type A (benzodiazepine and non-benzodiazepine agents) and some antidepressants. However, observational studies and meta-analyses indicate an increased mortality risk of anxiolytics and hypnotics, although bias may be involved due to confounding and high heterogeneity in these studies. Nevertheless, it seems that the risk incurred by the non-benzodiazepine hypnotic agents (Z drugs) may be relatively less than the risk of anxiolytics, with evidence indicating that at least one of these agents, zolpidem, may even confer a lower risk of mortality in adjusted models. All these issues are herein reviewed.

Cardiovascular Risk in Rheumatoid Arthritis and Mechanistic Links: From Pathophysiology to Treatment

2020 ◽  
Vol 18 (5) ◽  
pp. 431-446 ◽  
Author(s):  
George E. Fragoulis ◽  
Ismini Panayotidis ◽  
Elena Nikiphorou
Keyword(s):  
Rheumatoid Arthritis ◽  
Risk Factors ◽  
Current Evidence ◽  
Pharmacological Intervention ◽  
Cvd Risk ◽  
The Past ◽  
Increased Risk ◽  
Cv Disease ◽  
Obesity Hypertension ◽  
Inflammatory Burden

Rheumatoid arthritis (RA) is an autoimmune inflammatory arthritis. Inflammation, however, can spread beyond the joints to involve other organs. During the past few years, it has been well recognized that RA associates with increased risk for cardiovascular (CV) disease (CVD) compared with the general population. This seems to be due not only to the increased occurrence in RA of classical CVD risk factors and comorbidities like smoking, obesity, hypertension, diabetes, metabolic syndrome, and others but also to the inflammatory burden that RA itself carries. This is not unexpected given the strong links between inflammation and atherosclerosis and CVD. It has been shown that inflammatory cytokines which are present in abundance in RA play a significant role in every step of plaque formation and rupture. Most of the therapeutic regimes used in RA treatment seem to offer significant benefits to that end. However, more studies are needed to clarify the effect of these drugs on various parameters, including the lipid profile. Of note, although pharmacological intervention significantly helps reduce the inflammatory burden and therefore the CVD risk, control of the so-called classical risk factors is equally important. Herein, we review the current evidence for the underlying pathogenic mechanisms linking inflammation with CVD in the context of RA and reflect on the possible impact of treatments used in RA.

Effects of Maternal Diabetes on Fetal Expression of Insulin-Like Growth Factor and Insulin-Like Growth Factor Binding Protein MRNAs in the Rat

1995 ◽  
Vol 147 (2) ◽  
pp. R5-R8 ◽  
Author(s):  
Randal D. Streck ◽  
Veeraramani S. Rajaratnam ◽  
Renata B. Fishman ◽  
Peggy J. Webb
Keyword(s):  
Growth Factor ◽  
Mrna Expression ◽  
Fetal Growth ◽  
Fetal Liver ◽  
Expression Patterns ◽  
Maternal Diabetes ◽  
Limb Bud ◽  
Insulin Like Growth Factor ◽  
Igf Binding Proteins ◽  
Increased Risk

ABSTRACT Matemal diabetes is associated in humans and rats with an increased risk for fetal growth abnormalities and malformations. Therefore, the effect of maternal diabetes on expression of genes that regulate fetal growth and differentiation is of considerable interest. Developmental growth is regulated in part by the expression and availability of insulin-like growth factors (IGFs). Postnatal expression of a subset of the IGFs and IGF binding proteins (IGFBPs) has been demonstrated to be regulated in response to diabetes and other metabolic conditions. We used in situ hybridization to analyze the effect of maternal diabetes, induced by streptozotocin (STZ) prior to mating, upon prenatal rat IGF and IGFBP mRNA expression. At gestational day (GD) 14, the most striking effect of maternal diabetes on fetal IGF/IGFBP gene expression was a marked increase in the abundance of IGFBP-1 mRNA within the liver primordia of fetuses isolated from diabetic dams compared to age-matched controls. This upregulation cannot be entirely due to the approximately one-half-day delay in fetal development (based on limb bud staging) associated with maternal diabetes, as there was no gross difference in the level of IGFBP-1 mRNA between GD13 and GD14 control fetal livers. In contrast, the fetal mRNA expression patterns of IGF-I, IGF-II and IGFBP-2, -3, -4, -5 and -6 were not grossly altered by maternal diabetes. These data are consistent with the hypothesis that IGFBP-1 produced within the fetal liver and secreted into fetal circulation may play a role in regulating rat fetal growth.

Diabetes and pre-eclampsia affecting pregnancy: a retrospective cross-sectional study

2017 ◽  
Vol 66 (4) ◽  
pp. 728-732 ◽  
Author(s):  
Ram R Kalagiri ◽  
Niraj Vora ◽  
Jessica L Wilson ◽  
Syeda H Afroze ◽  
Venkata N Raju ◽  
...  
Keyword(s):  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Cross Sectional Study ◽  
Growth Restriction ◽  
Sectional Study ◽  
Placental Development ◽  
Cross Sectional ◽  
Diabetes Status ◽  
Elevated Glucose ◽  
Post Hoc

The interaction between pre-eclampsia and diabetes mellitus (DM) is far from being completely understood. In this study, we compared normal pregnancies with those complicated with pre-eclampsia, gestational DM, and/or pre-existing diabetes to assess the effects of hyperglycemia on placental development. AnInstitutional Review Board (IRB) approved retrospective cross-sectional study with 621 subjects was performed. Statistical analysis was performed using Duncan’s post hoc test and analysis of variance. Regardless of diabetes status, patients with pre-eclampsia delivered prematurely. Patients in the group with pre-eclampsia and pregestational diabetes delivered much earlier, at 35.0±0.4 weeks, when compared with the patients that had pre-eclampsia with gestational diabetes and pre-eclampsia with no diabetes (*P<0.05 for each). Additionally, patients with pre-existing diabetes who developed pre-eclampsia delivered smaller babies than those with pre-existing diabetes without pre-eclampsia (1.00±0.03, P<0.05 for each). Pre-existing diabetes with added insult of pre-eclampsia led to fetal growth restriction. This outcome validates the understanding that elevated glucose earlier in pregnancy alters placentogenesis and leads to fetal growth restriction.

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