The influence of the intrauterine environment on human placental development

Centre for Trophoblast Research, University of Cambridge, Cambridge, UK.
The International journal of developmental biology (Impact Factor: 1.9). 09/2009; 54(2-3):303-12. DOI: 10.1387/ijdb.082764gb
Source: PubMed


Development of the human placenta is modulated heavily by the intrauterine environment. During the first trimester, development takes place in a low oxygen environment supported by histiotrophic nutrition from the endometrial glands. Consequently, the rate of growth of the chorionic sac is almost invariable across this period, and is remarkably uniform between individuals. Towards the end of the first trimester the intrauterine environment undergoes radical transformation in association with onset of the maternal arterial circulation and the switch to haemotrophic nutrition. The accompanying rise in intraplacental oxygen concentration poses a major challenge to placental tissues, and extensive villous remodelling takes place at this time. Later in pregnancy a wide variety of stressors are capable of affecting placental growth, but in the human, the most common are nutrient deprivation and vascular compromise. The latter is usually secondary to deficient trophoblast invasion and can induce placental oxidative stress. Closely linked to oxidative stress is endoplasmic reticulum stress, and we recently provided the first evidence that the latter plays a major role in the pathophysiology of intrauterine growth restriction. The endoplasmic reticulum is a key regulator of protein synthesis, exerting its effects through the unfolded protein response. Consequently, we observed multiple blocks to translation initiation and elongation in growth restricted placentas. Nutrient deprivation also modulates protein synthesis through the mTOR pathway, and we demonstrated interactions between this pathway and endoplasmic reticulum stress. Protein synthesis inhibition therefore appears to be a common mechanism for regulating placental development under different adverse conditions.

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    • "By contrast, excessive ROS production results in oxidatively stressful conditions, inflammation, circulatory derangement, and placental bed cell apoptosis or necrosis. These events may occur transiently during labour in a fashion consistent with ischaemiareperfusion injury [26]; when lasting longer, or throughout the pregnancy, they may result in placental function impairment [27] [28] and serious pregnancy complications [24] [28]. Despite the likelihood of the process of ROS production, the identity and contribution of the redox players involved have remained unknown. "
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    ABSTRACT: Blood flow assessment employing Doppler techniques is a useful procedure in pregnancy evaluation, as it may predict pregnancy disorders coursing with increased uterine vascular impedance, as pre-eclampsia. While the local causes are unknown, emphasis has been put on reactive oxygen species (ROS) excessive production. As NADPH oxidase (NOX) is a ROS generator, it is hypothesized that combining Doppler assessment with NOX activity might provide useful knowledge on placental bed disorders underlying mechanisms. A prospective longitudinal study was performed in 19 normal course, singleton pregnancies. Fetal aortic isthmus (AoI) and maternal uterine arteries (UtA) pulsatility index (PI) were recorded at two time points: 20-22 and 40-41 weeks, just before elective Cesarean section. In addition, placenta and placental bed biopsies were performed immediately after fetal extraction. NOX activity was evaluated using a dihydroethidium-based fluorescence method and associations to PI values were studied with Spearman correlations. A clustering of pregnancies coursing with higher and lower PI values was shown, which correlated strongly with placental bed NOX activity, but less consistently with placental tissue. The study provides evidence favoring that placental bed NOX activity parallels UtA PI enhancement and suggests that an excess in oxidation underlies the development of pregnancy disorders coursing with enhanced UtA impedance. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
    04/2015; 5:114-123. DOI:10.1016/j.redox.2015.04.007
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    • "Placentation is an oxygen sensitive process. The events that occur from the time of implantation to maternal perfusion of the placenta are influenced and directed by site-specific oxygen tensions [22]. An oxygen gradient exists between the placenta and endometrium during the first trimester. "
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    ABSTRACT: A tenet of contemporary obstetrics is that events that compromise placentation increase the risk of complications of pregnancy and contribute to poor pregnancy outcome. In particular, conditions that affect the invasion of placental cells and remodeling of uterine spiral arteries compromise placental function and the subsequent development of the fetus. Extravillous trophoblast cells (EVTs) proliferate and migrate from the cytotrophoblast in the anchoring villi of the placenta and invade the maternal decidua and myometrium. These cells are localised with uterine uterine spiral arteries and are thought to induce vascular remodeling. A newly identified pathway by which EVTs may regulate vascular remodeling within the uterus is via the release of exosomes. Trophoblast cells release exosomes that mediate aspects of cell-to-cell communication. The aim of this brief commentary is to review the putative role of exosomes released from extravillous trophoblast cells in uterine spiral artery remodeling and, in particular, their role in the aetiology of preeclampsia. Placental exosomes may engage in local cell-to-cell communication between the cell constituents of the placenta and contiguous maternal tissues and/or distal interactions, involving the release of placental exosomes into biological fluids and their transport to a remote site of action.
    BioMed Research International 09/2014; 2014:693157. DOI:10.1155/2014/693157 · 2.71 Impact Factor
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    • "Preeclampsia and IUGR often arise from the common defect in placental development of impaired spiral artery remodeling [34,35]. This results in altered blood flow, and possible exposure of the developing fetus to a limited oxygen and nutrient supply. "
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    ABSTRACT: Background Sufficient amino acid transport activity (AAT) is indispensable for appropriate fetal growth. Studies suggest that placental nutrient uptake activity is responsive to both maternal and fetal nutrient demands. We hypothesize that under conditions of limited nutrient availability to the fetus, as often present in preeclampsia, intrauterine growth restriction (IUGR), and insufficient weight-gain during pregnancy, a general adaptive response aimed to increase amino acid transport activity may be observed in the placenta. Method A total of 40 placentas from full-term (n = 10) and pre-term (average gestational period = 34.8 weeks, n = 10) normal pregnancies, IUGR (n = 10), and preeclampsia (n = 10) associated pregnancies were looked at by immunohistochemistry followed by relative qualitative scoring to compare expression levels and localization of System L, ASCT2, and mTOR proteins. Result Microvillous syncytiotrophoblast (ST) in placenta of pregnancies complicated by IUGR or preeclampsia (PE) showed significant increases in the levels of System L amino acid transport proteins 4F2hc and LAT1 compared to both full-term control and pre-term (early gestation control) pregnancies seperately (p < 0.05). Elevated mTOR protein was uniquely higher in IUGR placentas compared to full-term controls (P = 0.0026). Total cellular ASCT2 transporter protein levels were similar in all groups, however, levels of ASCT2 protein localized to the ST microvillous membrane (MVM) were significantly lower in IUGR compared to both full-term and pre-term pregnancies (P = 0.0006, 0.03, respectively). Additionally, ASCT2 and mTOR protein levels were positively associated with maternal pre-pregnancy BMI (P = 0.046, 0.048, respectively). Conclusion There are three important findings based upon the present study. First, in conditions of limited nutrient availability, such as PE or IUGR, there is an overall increase in the level of System L and mTOR protein expression in the ST, suggestive of an adaptive response. Second, a decrease in ASCT2 protein at the ST MVM suggests a post-translational event that may decrease AAT activity in IUGR placentas. Third, a physiological link between transporter expression and pre-pregnancy BMI is suggested based upon a positive association observed with ASCT2 and mTOR expression values.
    BMC Pregnancy and Childbirth 05/2014; 14(1):181. DOI:10.1186/1471-2393-14-181 · 2.19 Impact Factor
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