DAAM2 is elevated in the circulation and placenta in pregnancies complicated by fetal growth restriction and is regulated by hypoxia

AbstractPreviously, we identified increased maternal circulating DAAM2 mRNA in pregnancies complicated by preterm fetal growth restriction (FGR). Here, we assessed whether circulating DAAM2 mRNA could detect FGR, and whether the DAAM2 gene, known to play roles in the Wnt signalling pathway is expressed in human placenta and associated with dysfunction and FGR. We performed linear regression analysis to calculate area under the ROC curve (AUC) for DAAM2 mRNA expression in the maternal circulation of pregnancies complicated by preterm FGR. DAAM2 mRNA expression was assessed across gestation by qPCR. DAAM2 protein and mRNA expression was assessed in preterm FGR placenta using western blot and qPCR. DAAM2 expression was assessed in term cytotrophoblasts and placental explant tissue cultured under hypoxic and normoxic conditions by qPCR. Small interfering RNAs were used to silence DAAM2 in term primary cytotrophoblasts. Expression of growth, apoptosis and oxidative stress genes were assessed by qPCR. Circulating DAAM2 mRNA was elevated in pregnancies complicated by preterm FGR [p < 0.0001, AUC = 0.83 (0.78–0.89)]. Placental DAAM2 mRNA was detectable across gestation, with highest expression at term. DAAM2 protein was increased in preterm FGR placentas but demonstrated no change in mRNA expression. DAAM2 mRNA expression was increased in cytotrophoblasts and placental explants under hypoxia. Silencing DAAM2 under hypoxia decreased expression of pro-survival gene, BCL2 and oxidative stress marker, NOX4, whilst increasing expression of antioxidant enzyme, HMOX-1. The increased DAAM2 associated with FGR and hypoxia implicates a potential role in placental dysfunction. Decreasing DAAM2 may have cytoprotective effects, but further research is required to elucidate its role in healthy and dysfunctional placentas.

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The Role of NFκB in Healthy and Preeclamptic Placenta: Trophoblasts in the Spotlight

International Journal of Molecular Sciences ◽

10.3390/ijms21051775 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1775 ◽

Cited By ~ 8

Author(s):

Brooke Armistead ◽

Leena Kadam ◽

Sascha Drewlo ◽

Hamid-Reza Kohan-Ghadr

Keyword(s):

Oxidative Stress ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Growth And Development ◽

Protein Family ◽

Growth Restriction ◽

Placental Development ◽

Critical Organ ◽

And Oxidative Stress

The NFκB protein family regulates numerous pathways within the cell—including inflammation, hypoxia, angiogenesis and oxidative stress—all of which are implicated in placental development. The placenta is a critical organ that develops during pregnancy that primarily functions to supply and transport the nutrients required for fetal growth and development. Abnormal placental development can be observed in numerous disorders during pregnancy, including fetal growth restriction, miscarriage, and preeclampsia (PE). NFκB is highly expressed in the placentas of women with PE, however its contributions to the syndrome are not fully understood. In this review we discuss the molecular actions and related pathways of NFκB in the placenta and highlight areas of research that need attention

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Maternal Undernourishment in Guinea Pigs Leads to Fetal Growth Restriction with Increased Hypoxic Cells and Oxidative Stress in the Brain

Developmental Neuroscience ◽

10.1159/000506939 ◽

2019 ◽

Vol 41 (5-6) ◽

pp. 290-299

Author(s):

Yohei Maki ◽

Karen Nygard ◽

Robert R. Hammond ◽

Timothy R.H. Regnault ◽

Bryan S. Richardson

Keyword(s):

Oxidative Stress ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Guinea Pigs ◽

Growth Restriction ◽

The Brain ◽

And Oxidative Stress

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Hypoxia and Oxidative Stress Are Associated with Reduced Fetal Growth in Twin and Undernourished Sheep Pregnancies

Animals ◽

10.3390/ani8110217 ◽

2018 ◽

Vol 8 (11) ◽

pp. 217 ◽

Cited By ~ 10

Author(s):

Francisco Sales ◽

Oscar Peralta ◽

Eileen Narbona ◽

Sue McCoard ◽

Mónica De los Reyes ◽

...

Keyword(s):

Oxidative Stress ◽

Birth Weight ◽

Low Birth Weight ◽

Cord Blood ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Growth Restriction ◽

Maternal Undernutrition ◽

Natural Pasture ◽

And Oxidative Stress

Low birth weight has profound implications for perinatal mortality and morbidity in lambs, causing higher mortality and lower growth potential. Low birth weight, as a consequence of fetal growth restriction, occurs in undernourished and multiple pregnancies, where hypoxia and oxidative stress could play a critical role. Our aim was to establish the effects of nutritional deprivation and pregnancy rank on fetal growth, oxygenation, and oxidative status in sheep pregnancies under extensive Patagonian conditions. At 30 days after mating, single- and twin-bearing ewes were offered only natural pasture (undernutrition group) or natural pasture plus concentrate supplementation (well-nourished group). At day 140 of gestation, blood gases and redox status were evaluated in venous cord blood, and fetal biometric characteristics were obtained after cesarean section. Both maternal undernutrition and twinning led to decreased oxygen supply to the fetuses (p = 0.016 and p = 0.050, respectively), which was associated with decreased intrauterine growth (r = 0.446, p < 0.01). Moreover, twinning increased oxidative stress in cord blood (p < 0.05), which might also contribute to fetal growth restriction. These results reinforce the importance of maternal nutrition, especially for those ewes bearing multiples, and opens new possibilities for nutritional or antioxidant interventions for preventing fetal hypoxia and oxidative stress.

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Effects of antenatal melatonin therapy on lung structure in growth-restricted newborn lambs

Journal of Applied Physiology ◽

10.1152/japplphysiol.00783.2016 ◽

2017 ◽

Vol 123 (5) ◽

pp. 1195-1203 ◽

Cited By ~ 8

Author(s):

Graeme R. Polglase ◽

Jade Barbuto ◽

Beth J. Allison ◽

Tamara Yawno ◽

Amy E. Sutherland ◽

...

Keyword(s):

Oxidative Stress ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Lung Development ◽

Fetal Lung ◽

Growth Restriction ◽

Fetal Sheep ◽

Respiratory Dysfunction ◽

Melatonin Administration ◽

Lung Structure

Oxidative stress arising from suboptimal placental function contributes to a multitude of pathologies in infants compromised by fetal growth restriction (FGR). FGR infants are at high risk for respiratory dysfunction after birth and poor long-term lung function. Our objective was to investigate the contribution of oxidative stress to adverse lung development and the effects of melatonin administration, a powerful antioxidant, on lung structure in FGR lambs. Placental insufficiency and FGR was surgically induced in 13 fetal sheep at ∼105 days of gestation by ligation of a single umbilical artery. Maternal intravenous melatonin infusion was commenced in seven of the ewes 4 h after surgery and continued until birth. Lambs delivered normally at term and lungs were collected 24 h after birth for histological assessment of lung structure and injury and compared with appropriately grown control lambs ( n = 8). FGR fetuses were hypoxic and had lower glucose during gestation compared with controls. Melatonin administration prevented chronic hypoxia. Within the lung, FGR caused reduced secondary septal crest density and altered elastin deposition compared with controls. Melatonin administration had no effect on the changes to lung structure induced by FGR. We conclude that chronic FGR disrupts septation of the developing alveoli, which is not altered by melatonin administration. These findings suggest that oxidative stress is not the mechanism driving altered lung structure in FGR neonates. Melatonin administration did not prevent disrupted airway development but also had no apparent adverse effects on fetal lung development. NEW & NOTEWORTHY Fetal growth restriction (FGR) results in poor respiratory outcomes, which may be caused by oxidation in utero. We investigated the contribution of oxidative stress to adverse lung development and the effects of melatonin administration, a powerful antioxidant, on lung structure in FGR lambs. FGR disrupted septation of the developing alveoli, which is not altered by melatonin administration. Oxidative stress may not be the mechanism driving altered lung structure in FGR neonates.

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Angiogenic Factors in Maternal Circulation and the Risk of Severe Fetal Growth Restriction

American Journal of Epidemiology ◽

10.1093/aje/kwq373 ◽

2011 ◽

Vol 173 (6) ◽

pp. 630-639 ◽

Cited By ~ 45

Author(s):

B. Olav Asvold ◽

L. J. Vatten ◽

P. R. Romundstad ◽

P. A. Jenum ◽

S. A. Karumanchi ◽

...

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Angiogenic Factors ◽

Growth Restriction ◽

Maternal Circulation

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Reduced placental prolyl hydroxylase 3 mRNA expression in pregnancies affected by fetal growth restriction

BJOG An International Journal of Obstetrics & Gynaecology ◽

10.1111/j.1471-0528.2010.02735.x ◽

2010 ◽

Vol 117 (13) ◽

pp. 1635-1642 ◽

Cited By ~ 5

Author(s):

V Gourvas ◽

S Sifakis ◽

E Dalpa ◽

N Soulitzis ◽

O Koukoura ◽

...

Keyword(s):

Mrna Expression ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Prolyl Hydroxylase ◽

Growth Restriction

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Effect of Endogenic and Exogenic Oxidative Stress Triggers on Adverse Pregnancy Outcomes: Preeclampsia, Fetal Growth Restriction, Gestational Diabetes Mellitus and Preterm Birth

International Journal of Molecular Sciences ◽

10.3390/ijms221810122 ◽

2021 ◽

Vol 22 (18) ◽

pp. 10122

Author(s):

Eun Hui Joo ◽

Young Ran Kim ◽

Nari Kim ◽

Jae Eun Jung ◽

Seon Ha Han ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Preterm Birth ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Fetal Growth ◽

Pregnancy Outcomes ◽

Fetal Growth Restriction ◽

Growth Restriction ◽

Adverse Pregnancy

Oxidative stress is caused by an imbalance between the production of reactive oxygen species (ROS) in cells and tissues and the ability of a biological system to detoxify them. During a normal pregnancy, oxidative stress increases the normal systemic inflammatory response and is usually well-controlled by the balanced body mechanism of the detoxification of anti-oxidative products. However, pregnancy is also a condition in which this adaptation and balance can be easily disrupted. Excessive ROS is detrimental and associated with many pregnancy complications, such as preeclampsia (PE), fetal growth restriction (FGR), gestational diabetes mellitus (GDM), and preterm birth (PTB), by damaging placentation. The placenta is a tissue rich in mitochondria that produces the majority of ROS, so it is important to maintain normal placental function and properly develop its vascular network to ensure a safe and healthy pregnancy. Antioxidants may ameliorate these diseases, and related research is progressing. This review aimed to determine the association between oxidative stress and adverse pregnancy outcomes, especially PE, FGR, GDM, and PTB, and explore how to overcome this oxidative stress in these unfavorable conditions.

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The role of melatonin in pregnancies complicated by placental insufficiency: a systematic review

10.22541/au.161790597.72492340/v1 ◽

2021 ◽

Author(s):

Ilaria Fantasia ◽

Sofia Bussolaro ◽

Tamara Stampalija ◽

Daniel Rolnik

Keyword(s):

Oxidative Stress ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Evidence Synthesis ◽

Placental Insufficiency ◽

Growth Restriction ◽

Melatonin Receptors ◽

Qualitative Evidence Synthesis ◽

Melatonin Administration

Background: Pregnancies complicated by placental insufficiency are characterised by increased oxidative stress. It has been suggested that melatonin has antioxidant properties and contributes to the maintenance of placental homeostasis. Objective: To systematically review the available literature about melatonin in pregnancies complicated by placental insufficiency, specifically preeclampsia and fetal growth restriction, exploring three different aspects: 1) maternal melatonin levels; 2) expression and activity of melatonin placental receptors; 3) effects of maternal melatonin administration. Search strategy: PubMed (Medline) and Scopus were searched until December 2020. Selection criteria: Published literature in English language describing the role of melatonin in pregnancies complicated by placental insufficiency, with a specific focus on preeclampsia and fetal growth restriction. Data collection and analysis: Identified studies were screened and assessed independently by two authors. Data were extracted and compiled in a qualitative evidence synthesis. Main results: Pregnancies complicated by placental insufficiency show a significant reduction in maternal systemic serum melatonin levels and a significant reduction in the expression of placental melatonin receptors. Melatonin administration in pregnancy seems safe and may reduce oxidative stress. Conclusion: The circadian pattern of melatonin secretion seems to be altered in pregnancies complicated by placental insufficiency. This is reflected by lower production of melatonin, with consequent lower systemic and placental concentrations, and lower expression of melatonin receptors, thus reducing the local release of the indole and its autocrine function. Funding: None Keywords: Melatonin, Preeclampsia, Fetal growth restriction, Placental insufficiency, Review.

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