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      Placental adaptations supporting fetal growth during normal and adverse gestational environments

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          Abstract

          The placenta is vital for mammalian development and a key determinant of life‐long health. It is the interface between the mother and fetus and is responsible for transporting the nutrients and oxygen a fetus needs to develop and grow. Alterations in placental formation and function, therefore, have consequences for fetal growth and birthweight, which in turn determine perinatal survival and risk of non‐communicable diseases for the offspring in later postnatal life. However, the placenta is not a static organ. As this review summarizes, research from multiple species has demonstrated that placental formation and function alter developmentally to the needs of the fetus for substrates for growth during normal gestation, as well as when there is greater competition for substrates in polytocous species and monotocous species with multiple gestations. The placenta also adapts in response to the gestational environment, integrating information about the ability of the mother to provide nutrients and oxygen with the needs of the fetus in that prevailing environment. In particular, placental structure (e.g. vascularity, surface area, blood flow, diffusion distance) and transport capacity (e.g. nutrient transporter levels and activity) respond to suboptimal gestational environments, namely malnutrition, obesity, hypoxia and maternal ageing. Mechanisms mediating developmentally and environmentally induced homeostatic responses of the placenta that help support normal fetal growth include imprinted genes, signalling pathways, subcellular constituents and fetal sexomes. Identification of these placental strategies may inform the development of therapies for complicated human pregnancies and advance understanding of the pathways underlying poor fetal outcomes and their consequences for health and disease risk.

          Abstract

          • What is the topic of this review?

            How the placenta, which transports nutrients and oxygen to the fetus, may alter its support of fetal growth developmentally and with adverse gestational conditions.

          • What advances does it highlight?

            Placental formation and function alter with the needs of the fetus for substrates for growth during normal gestation and when there is enhanced competition for substrates in species with multiple gestations or adverse gestational environments, and this is mediated by imprinted genes, signalling pathways, mitochondria and fetal sexomes.

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          Most cited references194

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          Role of insulin-like growth factors in embryonic and postnatal growth.

          A developmental analysis of growth kinetics in mouse embryos carrying null mutations of the genes encoding insulin-like growth factor I (IGF-I), IGF-II, and the type 1 IGF receptor (IGF1R), alone or in combination, defined the onset of mutational effects leading to growth deficiency and indicated that between embryonic days 11.0 and 12.5, IGF1R serves only the in vivo mitogenic signaling of IGF-II. From E13.5 onward, IGF1R interacts with both IGF-I and IGF-II, while IGF-II recognizes an additional unknown receptor (XR). In contrast with the embryo proper, placental growth is served exclusively by an IGF-II-XR interaction. Additional genetic data suggested that the type 2IGF/mannose 6-phosphate receptor is an unlikely candidate for XR. Postnatal growth curves indicated that surviving Igf-1(-/-) mutants, which are infertile and exhibit delayed bone development, continue to grow with a retarded rate after birth in comparison with wild-type littermates and become 30% of normal weight as adults.
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            Review: Sex and the human placenta: mediating differential strategies of fetal growth and survival.

            There are known sex specific differences in fetal and neonatal morbidity and mortality. There are also known differences in birthweight centile with males generally being larger than females at birth. These differences are generally ignored when studying obstetric complications of pregnancy and the mechanisms that confer these differences between the sexes are unknown. Current evidence suggests sex specific adaptation of the placenta may be central to the differences in fetal growth and survival. Our research examining pregnancies complicated by asthma has reported sexually dimorphic differences in fetal growth and survival with males adapting placental function to allow for continued growth in an adverse maternal environment while females reduce growth in an attempt to survive further maternal insults. We have reported sex differences in placental cytokine expression, insulin-like growth factor pathways and the placental response to cortisol in relation to the complication of asthma during pregnancy. More recently we have identified sex specific alterations in placental function in pregnancies complicated by preterm delivery which were associated with neonatal outcome and survival. We propose the sexually dimorphic differences in growth and survival of the fetus are mediated by the sex specific function of the human placenta. This review will present evidence supporting this hypothesis and will argue that to ignore the sex of the placenta is no longer sound scientific practice. Crown Copyright 2010. Published by Elsevier Ltd. All rights reserved.
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              Activation of placental mTOR signaling and amino acid transporters in obese women giving birth to large babies.

              Babies of obese women are often large at birth, which is associated with perinatal complications and metabolic syndrome later in life. The mechanisms linking maternal obesity to fetal overgrowth are largely unknown. We tested the hypothesis that placental insulin/IGF-I and mammalian target of rapamycin (mTOR) signaling is activated and amino acid transporter activity is increased in large babies of obese women. Pregnant women were recruited prospectively for collection of placental tissue at a university hospital and academic biomedical center. Twenty-three Swedish pregnant women with first trimester body mass index ranging from 18.5 to 44.9 kg/m(2) and with uncomplicated pregnancies participated in the study. There were no interventions. We determined the phosphorylation of key signaling molecules (including Akt, IRS-1, S6K1, 4EBP-1, RPS6, and AMPK) in the placental insulin/IGF-I, AMPK, and mTOR signaling pathways. The activity and protein expression of the amino acid transporter systems A and L were measured in syncytiotrophoblast microvillous plasma membranes. Birth weights (range, 3025-4235 g) were positively correlated to maternal body mass index (P < 0.05). The activity of placental insulin/IGF-I and mTOR signaling was positively correlated (P < 0.001), whereas AMPK phosphorylation was inversely (P < 0.05) correlated to birth weight. Microvillous plasma membrane system A, but not system L, activity and protein expression of the system A isoform SNAT2 were positively correlated to birth weight (P < 0.001). Up-regulation of specific placental amino acid transporter isoforms may contribute to fetal overgrowth in maternal obesity. This effect may be mediated by activation of insulin/IGF-I and mTOR signaling pathways, which are positive regulators of placental amino acid transporters.
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                Author and article information

                Contributors
                ans48@cam.ac.uk
                Journal
                Exp Physiol
                Exp Physiol
                10.1111/(ISSN)1469-445X
                EPH
                expphysiol
                Experimental Physiology
                John Wiley and Sons Inc. (Hoboken )
                0958-0670
                1469-445X
                09 December 2022
                March 2023
                : 108
                : 3 ( doiID: 10.1113/eph.v108.3 )
                : 371-397
                Affiliations
                [ 1 ] Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience University of Cambridge Cambridge UK
                [ 2 ] Facultad de Ciencias Departamento de Ciencias Básicas, Universidad Santo Tomás Valdivia Chile
                Author notes
                [*] [* ] Correspondence

                Amanda Sferruzzi‐Perri, Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.

                Email: ans48@ 123456cam.ac.uk

                Author information
                https://orcid.org/0000-0002-4931-4233
                Article
                EPH13282
                10.1113/EP090442
                10103877
                36484327
                730ffe05-4880-470b-a8d2-593a4bdd331c
                © 2022 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 21 September 2022
                : 15 November 2022
                Page count
                Figures: 2, Tables: 4, Pages: 27, Words: 17355
                Funding
                Funded by: MRC New Investigator Grant
                Award ID: MR/R022690/1/RG93186
                Funded by: Lister Institute of Preventative Medicine Research Prize
                Award ID: RG93692
                Funded by: Wellcome Trust Henry Wellcome Postdoctoral Fellowship
                Award ID: 220456/Z/20/Z
                Funded by: Beca‐Chile, ANID Postdoctoral Scholarship
                Award ID: 74190055
                Categories
                2022 Mid‐career Researcher Prize Runner‐up
                Reviews
                Custom metadata
                2.0
                1 March 2023
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.4.0 mode:remove_FC converted:02.04.2024

                Anatomy & Physiology
                ageing,fetus,hypoxia,malnutrition,mitochondria,nutrient,obesity,placenta,pregnancy,sex differences

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