scholarly journals Angiogenesis in the Placenta: The Role of Reactive Oxygen Species Signaling

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Robyn D. Pereira ◽  
Nicole E. De Long ◽  
Ruijun C. Wang ◽  
Fereshteh T. Yazdi ◽  
Alison C. Holloway ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factors ◽  
Maternal Obesity ◽  
Placental Development ◽  
Placental Dysfunction ◽  
Placental Angiogenesis ◽  
Healthy Pregnancy ◽  
Adverse Pregnancy ◽  
And Function ◽  
Reactive Oxygen Species Signaling

Proper placental development and function are central to the health of both the mother and the fetus during pregnancy. A critical component of healthy placental function is the proper development of its vascular network. Poor vascularization of the placenta can lead to fetal growth restriction, preeclampsia, and in some cases fetal death. Therefore, understanding the mechanisms by which uterine stressors influence the development of the placental vasculature and contribute to placental dysfunction is of central importance to ensuring a healthy pregnancy. In this review we discuss how oxidative stress observed in maternal smoking, maternal obesity, and preeclampsia has been associated with aberrant angiogenesis and placental dysfunction resulting in adverse pregnancy outcomes. We also highlight that oxidative stress can influence the expression of a number of transcription factors important in mediating angiogenesis. Therefore, understanding how oxidative stress affects redox-sensitive transcription factors within the placenta may elucidate potential therapeutic targets for correcting abnormal placental angiogenesis and function.

Effects of Maternal Obesity and Gestational Diabetes Mellitus on the Placenta: Current Knowledge and Targets for Therapeutic Interventions

2020 ◽  
Vol 19 (2) ◽  
pp. 176-192
Author(s):  
Samantha Bedell ◽  
Janine Hutson ◽  
Barbra de Vrijer ◽  
Genevieve Eastabrook
Keyword(s):  
Diabetes Mellitus ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Maternal Obesity ◽  
Environmental Changes ◽  
Current Knowledge ◽  
Therapeutic Interventions ◽  
Placental Development ◽  
Exchange Site ◽  
And Function

: Obesity and gestational diabetes mellitus (GDM) are becoming more common among pregnant women worldwide and are individually associated with a number of placenta-mediated obstetric complications, including preeclampsia, macrosomia, intrauterine growth restriction and stillbirth. The placenta serves several functions throughout pregnancy and is the main exchange site for the transfer of nutrients and gas from mother to fetus. In pregnancies complicated by maternal obesity or GDM, the placenta is exposed to environmental changes, such as increased inflammation and oxidative stress, dyslipidemia, and altered hormone levels. These changes can affect placental development and function and lead to abnormal fetal growth and development as well as metabolic and cardiovascular abnormalities in the offspring. This review aims to summarize current knowledge on the effects of obesity and GDM on placental development and function. Understanding these processes is key in developing therapeutic interventions with the goal of mitigating these effects and preventing future cardiovascular and metabolic pathology in subsequent generations.

scholarly journals MEF2 transcription factors in human placenta and involvement in cytotrophoblast invasion and differentiation

2018 ◽  
Vol 50 (1) ◽  
pp. 10-19 ◽  
Author(s):  
Lucy Li ◽  
Lewis P. Rubin ◽  
Xiaoming Gong
Keyword(s):  
Transcription Factors ◽  
Human Placenta ◽  
Cellular Proliferation ◽  
Cell Types ◽  
Dominant Negative ◽  
Trophoblast Invasion ◽  
Placental Development ◽  
Cytotrophoblast Cell ◽  
Adverse Pregnancy

Development of the human placenta and its trophoblast cell types is critical for a successful pregnancy. Defects in trophoblast invasion and differentiation are associated with adverse pregnancy outcomes, including preeclampsia. The members of myocyte enhancer factor-2 (MEF2) family of transcription factors are key regulators of cellular proliferation, differentiation, and invasion in various cell types and tissues and might play a similarly important role in regulating trophoblast proliferation, invasion, and differentiation during human placental development. In the present study, using human cytotrophoblast cell lines (HTR8/SVneo and BeWo) and primary human cytotrophoblasts (CTBs), we show that members of the MEF2 family are differentially expressed in human placental CTBs, with MEF2B and MEF2D being highly expressed in first trimester extravillous CTBs. Overexpression of MEF2D results in cytotrophoblast proliferation and enhances the invasion and migration of extravillous-like HTR8/SVneo cells. This invasive property is blocked by overexpression of a dominant negative MEF2 (dnMEF2). In contrast, MEF2A is the principal MEF2 isoform expressed in term CTBs, MEF2C and MEF2D being expressed more weakly, and MEF2B expression being undetected. Overexpression of MEF2A induces cytotrophoblast differentiation and syncytium formation in BeWo cells. During in vitro differentiation of primary CTBs, MEF2A expression is associated with CTB differentiation into syncytiotrophoblast. Additionally, the course of p38 MAPK and ERK5 activities parallels the increase in MEF2A expression. These findings suggest individual members of MEF2 family distinctively regulate cytotrophoblast proliferation, invasion, and differentiation. Dysregulation of expression of MEF2 family or of their upstream signaling pathways may be associated with placenta-related pregnancy disorders.

scholarly journals The Importance of Antioxidant Micronutrients in Pregnancy

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Hiten D. Mistry ◽  
Paula J. Williams
Keyword(s):  
Oxidative Stress ◽  
Placental Development ◽  
Maternal Circulation ◽  
Copper Zinc ◽  
Adverse Pregnancy ◽  
Intervention Trials ◽  
Peroxidase Enzymes ◽  
Reduced Activity ◽  
In Pregnancy

Pregnancy places increased demands on the mother to provide adequate nutrition to the growing conceptus. A number of micronutrients function as essential cofactors for or themselves acting as antioxidants. Oxidative stress is generated during normal placental development; however, when supply of antioxidant micronutrients is limited, exaggerated oxidative stress within both the placenta and maternal circulation occurs, resulting in adverse pregnancy outcomes. The present paper summarises the current understanding of selected micronutrient antioxidants selenium, copper, zinc, manganese, and vitamins C and E in pregnancy. To summarise antioxidant activity of selenium is via its incorporation into the glutathione peroxidase enzymes, levels of which have been shown to be reduced in miscarriage and preeclampsia. Copper, zinc, and manganese are all essential cofactors for superoxide dismutases, which has reduced activity in pathological pregnancy. Larger intervention trials are required to reinforce or refute a beneficial role of micronutrient supplementation in disorders of pregnancies.

scholarly journals Lipotoxicity in obese pregnancy and its potential role in adverse pregnancy outcome and obesity in the offspring

2010 ◽  
Vol 119 (3) ◽  
pp. 123-129 ◽  
Author(s):  
Eleanor Jarvie ◽  
Sylvie Hauguel-de-Mouzon ◽  
Scott M. Nelson ◽  
Naveed Sattar ◽  
Patrick M. Catalano ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Fatty Acids ◽  
Endothelial Dysfunction ◽  
Maternal Obesity ◽  
Adverse Pregnancy Outcome ◽  
Oxidized Lipids ◽  
Lower Body ◽  
Adverse Pregnancy ◽  
And Oxidative Stress

Increasing maternal obesity is a challenge that has an impact on all aspects of female reproduction. Lean and obese pregnant women gain similar fat mass, but lean women store fat in the lower-body compartment and obese women in central compartments. In the non-pregnant, central storage of fat is associated with adipocyte hypertrophy and represents a failure to adequately store excess fatty acids, resulting in metabolic dysregulation and ectopic fat accumulation (lipotoxicity). Obese pregnancy is associated with exaggerated metabolic adaptation, endothelial dysfunction and increased risk of adverse pregnancy outcome. We hypothesize that the preferential storage of fat in central rather than ‘safer’ lower-body depots in obese pregnancy leads to lipotoxicity. The combination of excess fatty acids and oxidative stress leads to the production of oxidized lipids, which can be cytotoxic and influence gene expression by acting as ligands for nuclear receptors. Lipid excess and oxidative stress provoke endothelial dysfunction. Oxidized lipids can inhibit trophoblast invasion and influence placental development, lipid metabolism and transport and can also affect fetal developmental pathways. As lipotoxicity has the capability of influencing both maternal endothelial function and placental function, it may link maternal obesity and placentally related adverse pregnancy outcomes such as miscarriage and pre-eclampsia. The combination of excess/altered lipid nutrient supply, suboptimal in utero metabolic environment and alterations in placental gene expression, inflammation and metabolism may also induce obesity in the offspring.

scholarly journals Regulation of vascular growth and function in the human placenta

Reproduction ◽  
2009 ◽  
Vol 138 (6) ◽  
pp. 895-902 ◽  
Author(s):  
G J Burton ◽  
D S Charnock-Jones ◽  
E Jauniaux
Keyword(s):  
Oxidative Stress ◽  
Growth Factor ◽  
Human Placenta ◽  
Normal Pregnancy ◽  
Maternal Circulation ◽  
Placental Angiogenesis ◽  
Terminal Villi ◽  
And Function ◽  
Endothelial Growth Factor ◽  
The Impact

During the course of 9 months, the human placenta develops into a highly vascular organ. Vasculogenesis starts during the third week post-conception. Hemangioblastic cell cords differentiatein situfrom mesenchymal cells in the villous cores, most probably under the influence of vascular endothelial growth factor (VEGFA) secreted by the overlying trophoblast. The cords elongate through proliferation and cell recruitment, and connect with the vasculature of the developing fetus. A feto-placental circulation starts around 8 weeks of gestation. Elongation of the capillaries outstrips that of the containing villi, leading to looping of the vessels. The obtrusion of both capillary loops and new sprouts results in the formation of terminal villi. Branching and non-branching angiogenesis therefore play key roles in villous morphogenesis throughout pregnancy. Maternal circulating levels of VEGFA and placental growth factor vary across normal pregnancy, and in complicated pregnancies. Determining the impact of these changes on placental angiogenesis is difficult, as the relationship between levels of factors in the maternal circulation and their effects on fetal vessels within the placenta remains unclear. Furthermore, the trophoblast secretes large quantities of soluble receptors capable of binding both growth factors, influencing their bioavailability. Villous endothelial cells are prone to oxidative stress, which activates the apoptotic cascade. Oxidative stress associated with onset of the maternal circulation, and with incomplete conversion of the spiral arteries in pathological pregnancies, plays an important role in sculpting the villous tree. Suppression of placental angiogenesis results in impoverished development of the placenta, leading ultimately to fetal growth restriction.

scholarly journals Association of Polybrominated Diphenyl Ether (PBDE) Levels with Biomarkers of Placental Development and Disease during Mid-gestation

2019 ◽  
Author(s):  
Julia Varshavsky ◽  
Joshua F. Robinson ◽  
Yan Zhou ◽  
Kenisha A. Puckett ◽  
Elaine Kwan ◽  
...  
Keyword(s):  
Diphenyl Ether ◽  
Antigen Expression ◽  
Polybrominated Diphenyl Ether ◽  
Environmental Chemicals ◽  
Vascular Endothelial ◽  
Placental Development ◽  
Regression Methods ◽  
Specific Antigens ◽  
Adverse Pregnancy ◽  
And Function

Abstract BackgroundPolybrominated diphenyl ether (PBDE) exposures have been associated with adverse pregnancy outcomes. A hypothesized mechanism is via alterations in placental development and function. However, we lack biomarkers that can be used as early indicators of maternal/fetal response to PBDE exposures and/or perturbations in placental development or function. MethodsTo evaluate the relationship between PBDE levels and placental biomarkers during mid-gestation of human pregnancy (n = 62), we immunolocalized three molecules that play key roles in cytotrophoblast (CTB) differentiation and interstitial/endovascular uterine invasion—integrin alpha-1 (ITGA1), vascular endothelial-cadherin (CDH5), and metalloproteinase-1 (MMP1)–and assessed three morphological parameters as potential indicators of pathological alterations using H&E-stained tissues–leukocyte infiltration, fibrinoid deposition, and CTB endovascular invasion. We evaluated associations between placental PBDE levels and of biomarkers of placental development and disease using censored Kendall’s tau correlation and linear regression methods. ResultsPBDEs were detected in all placental samples. We observed substantial variation in antigen expression and morphological endpoints across placental regions. We observed an association between PBDE levels and immunoreactivity of endovascular CTB staining with anti-ITGA1 (inverse) or interstitial CTBs staining with anti-CDH5 (positive). ConclusionsWe found several molecular markers that may be sensitive placental indicators of PBDE exposure. Further, this indicates that placental biomarkers of development and disease could be useful barometers of exposure to PBDEs, a paradigm that could be extended to other environmental chemicals and placental stage-specific antigens.

scholarly journals Palmitic acid induces inflammation in placental trophoblasts and impairs their migration toward smooth muscle cells through plasminogen activator inhibitor-1

2020 ◽  
Vol 26 (11) ◽  
pp. 850-865
Author(s):  
Amanda M Rampersaud ◽  
Caroline E Dunk ◽  
Stephen J Lye ◽  
Stephen J Renaud
Keyword(s):  
Smooth Muscle ◽  
Inflammatory Response ◽  
Smooth Muscle Cells ◽  
Palmitic Acid ◽  
Maternal Obesity ◽  
Muscle Cells ◽  
Trophoblast Invasion ◽  
Migration And Invasion ◽  
Placental Development ◽  
Placental Dysfunction

Abstract A critical component of early human placental development includes migration of extravillous trophoblasts (EVTs) into the decidua. EVTs migrate toward and displace vascular smooth muscle cells (SMCs) surrounding several uterine structures, including spiral arteries. Shallow trophoblast invasion features in several pregnancy complications including preeclampsia. Maternal obesity is a risk factor for placental dysfunction, suggesting that factors within an obese environment may impair early placental development. Herein, we tested the hypothesis that palmitic acid, a saturated fatty acid circulating at high levels in obese women, induces an inflammatory response in EVTs that hinders their capacity to migrate toward SMCs. We found that SMCs and SMC-conditioned media stimulated migration and invasion of an EVT-like cell line, HTR8/SVneo. Palmitic acid impaired EVT migration and invasion toward SMCs, and induced expression of several vasoactive and inflammatory mediators in EVTs, including endothelin, interleukin (IL)-6, IL-8 and PAI1. PAI1 was increased in plasma of women with early-onset preeclampsia, and PAI1-deficient EVTs were protected from the anti-migratory effects of palmitic acid. Using first trimester placental explants, palmitic acid exposure decreased EVT invasion through Matrigel. Our findings reveal that palmitic acid induces an inflammatory response in EVTs and attenuates their migration through a mechanism involving PAI1. High levels of palmitic acid in pathophysiological situations like obesity may impair early placental development and predispose to placental dysfunction.

scholarly journals The potential role of the ERRγ pathway in placental dysfunction

Reproduction ◽  
2020 ◽  
Author(s):  
Zhiyong Zou ◽  
Karen Forbes ◽  
Lynda K. Harris ◽  
Alexander E P Heazell
Keyword(s):  
Fetal Growth ◽  
Therapeutic Interventions ◽  
Placental Development ◽  
Human Trophoblast ◽  
Altered Expression ◽  
Placental Dysfunction ◽  
And Function ◽  
Upstream Regulators ◽  
Estrogen Related Receptor

Normal placental development and function is of key importance to fetal growth. Conversely aberrations of placental structure and function are evident in pregnancy complications including fetal growth restriction (FGR) and preeclampsia. Although trophoblast turnover and function is altered in these conditions, their underlying aetiologies and pathophysiology remains unclear, which hampers development of therapeutic interventions. Here we review evidence that supports a role for Estrogen Related Receptor-gamma (ERRγ) in the development of placental dysfunction in FGR and preeclampsia. This relationship deserves particular consideration because ERRγ is highly expressed in normal placenta, is reduced in FGR and preeclampsia and its expression is altered by hypoxia, which is thought to result from deficient placentation seen in FGR and preeclampsia. Several studies have also found microRNA or other potential upstream regulators of ERRγ negatively influence trophoblast function which could contribute to placental dysfunction seen in FGR and preeclampsia. Interestingly, microRNAs regulate ERRγ expression in human trophoblast. Thus, if ERRγ is pivotally associated with the abnormal trophoblast turnover and function it may be targeted by microRNAs or other possible upstream regulators in the placenta. This review explores altered expression of ERRγ and upstream regulation of ERRγ-mediated pathways resulting in the trophoblast turnover, placental vascularisation, and placental metabolism underlying placental dysfunctions. This demonstrates that the ERRγ pathway merits further investigation as a potential therapeutic target in FGR and preeclampsia.

scholarly journals The Impact of Hypoxia in Early Pregnancy on Placental Cells

2021 ◽  
Vol 22 (18) ◽  
pp. 9675
Author(s):  
Hui Zhao ◽  
Ronald J. Wong ◽  
David K. Stevenson
Keyword(s):  
Stem Cells ◽  
First Trimester ◽  
Low Oxygen ◽  
Placental Development ◽  
Trophoblast Stem Cells ◽  
Oxygen Levels ◽  
Trophoblast Stem ◽  
Adverse Pregnancy ◽  
And Function ◽  
The Impact

Oxygen levels in the placental microenvironment throughout gestation are not constant, with severe hypoxic conditions present during the first trimester. This hypoxic phase overlaps with the most critical stages of placental development, i.e., blastocyst implantation, cytotrophoblast invasion, and spiral artery remodeling initiation. Dysregulation of any of these steps in early gestation can result in pregnancy loss and/or adverse pregnancy outcomes. Hypoxia has been shown to regulate not only the self-renewal, proliferation, and differentiation of trophoblast stem cells and progenitor cells, but also the recruitment, phenotype, and function of maternal immune cells. In this review, we will summarize how oxygen levels in early placental development determine the survival, fate, and function of several important cell types, e.g., trophoblast stem cells, extravillous trophoblasts, syncytiotrophoblasts, uterine natural killer cells, Hofbauer cells, and decidual macrophages. We will also discuss the cellular mechanisms used to cope with low oxygen tensions, such as the induction of hypoxia-inducible factor (HIF) or mammalian target of rapamycin (mTOR) signals, regulation of the metabolic pathway, and adaptation to autophagy. Understanding the beneficial roles of hypoxia in early placental development will provide insights into the root cause(s) of some pregnancy disorders, such as spontaneous abortion, preeclampsia, and intrauterine growth restriction.

scholarly journals Maternal Obesity Increases Oxidative Stress in Placenta and It Is Associated With Intestinal Microbiota

2021 ◽  
Vol 11 ◽  
Author(s):  
Chengjun Hu ◽  
Yingli Yan ◽  
Fengjie Ji ◽  
Hanlin Zhou
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Response ◽  
Intestinal Microbiota ◽  
Maternal Obesity ◽  
Citrate Synthase ◽  
Obese Group ◽  
Backfat Thickness ◽  
Microbiota Composition ◽  
Placental Dysfunction ◽  
Placental Oxidative Stress

Maternal obesity induces placental dysfunction and intestinal microbial dysbiosis. However, the associations between intestinal microbiota and placental dysfunction are still unclear. In the present study, a gilt model was used to investigate the role of maternal obesity on placental oxidative stress, mitochondrial function, and fecal microbiota composition, meanwhile identifying microbiota markers associated with placental oxidative stress. Twenty gilts were divided into two groups based on their backfat thickness on parturition day: namely Con group (average backfat thickness = 33 mm), and Obese group (average backfat thickness = 39 mm). The results showed that Obese group was lower than Con group in the birth weight of piglets. Compared with the Con group, the Obesity group exhibited an increased oxidative damage and inflammatory response in placenta, as evidenced by the increased concentrations of placental reactive oxygen species (ROS), protein carboxyl, and interleukin-6 (IL-6). Obesity group was lower than Con group in the concentrations of placental adenosine triphosphate, citrate synthase, and complex I activity. In addition, lower propionate level and Bacteroidetes abundance in feces were seen in the Obese Group. Furthermore, the concentrations of placental ROS, protein carboxyl, and IL-6 were positively correlated with the abundance of Christensenellaceae_R-7_group and negatively correlated with that of norank_f_Bacteroidales_S24-7_group. In conclusion, these findings suggest that maternal obesity might impair oxidative and inflammatory response in placenta through modulating intestinal microbiota composition.

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