Journal articles on the topic 'Placental proteins'
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1
Zhang, Yi, Yunhui Tang, Xinyi Sun, Matt Kang, Min Zhao, Jiayi Wan, and Qi Chen. "Exporting Proteins Associated with Senescence Repair via Extracellular Vesicles May Be Associated with Early Pregnancy Loss." Cells 11, no. 18 (September 6, 2022): 2772. http://dx.doi.org/10.3390/cells11182772.
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Introduction: Dysfunction of placental development is involved in early pregnancy loss. Senescent changes have been seen in missed miscarriage, one type of pregnancy loss. Extracellular vesicles (EVs) have been widely implicated in the pathogenesis of diseases. In this study, we investigated the protein profiles in placental EVs derived from missed miscarriage in comparison with healthy pregnancy. We also investigated whether cargos packed into EVs are involved in the dysfunctional development of the placenta seen in missed miscarriage. Methods: Proteomic analysis of placental EVs derived from healthy and missed-miscarriage placentae was performed. Three senescence-repair-associated proteins, replication protein A-70 (RPA-70), proteasome activator subunit-4 (PMSE-4), and protein activated kinase-2, (PAK-2) were examined in placental EVs and placentae, and in placental explants that had been treated with or without GW4869, by western blotting and immunohistochemistry. Results: The total number of proteins associated with placental EVs was not different between the two groups. However, there were 106 and 151 abundantly expressed proteins associated with placental micro- or nano-EVs from missed miscarriage in comparison with EVs from controls. Of these abundant proteins, 59 and 81 proteins in placental micro- or nano-EVs, respectively, are associated with DNA damage/repair and cell death/survival. We further found higher levels of three senescence-repair-associated proteins (RPA-70, PMSE-4, and PAK-2) associated with placental EVs, but lower levels of these proteins in missed-miscarriage placentae. Regarding inhibition of EV formation or release by GW4869, we found that the expression of these three proteins was higher in GW4869-treated placental explants from missed miscarriage. Discussion: Our data may suggest that “inadvertently” sorting of cargos and exporting proteins associated with senescence-repair by placental EVs may be associated with the dysfunction of placental development seen in missed miscarriage.
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Tang, Yunhui, Katie Groom, Larry Chamley, and Qi Chen. "Melatonin, a Potential Therapeutic Agent for Preeclampsia, Reduces the Extrusion of Toxic Extracellular Vesicles from Preeclamptic Placentae." Cells 10, no. 8 (July 27, 2021): 1904. http://dx.doi.org/10.3390/cells10081904.
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Preeclampsia, characterised by maternal endothelial cell activation, is triggered by toxic factors, such as placental extracellular vesicles (EVs) from a dysfunctional placenta. The increased oxidative stress seen in the preeclamptic placenta links to endoplasmic reticulum (ER) stress. The ER regulates protein folding and trafficking. When the ER is stressed, proteins are misfolded, and misfolded proteins are toxic. Misfolded proteins can be exported from cells, via EVs which target to other cells where the misfolded proteins may also be toxic. Melatonin is a hormone and antioxidant produced by the pineal gland and placenta. Levels of melatonin are reduced in preeclampsia. In this study we investigated whether melatonin treatment can change the nature of placental EVs that are released from a preeclamptic placenta. EVs were collected from preeclamptic (n = 6) and normotensive (n = 6) placental explants cultured in the presence or absence of melatonin for 18 h. Misfolded proteins were measured using a fluorescent compound, Thioflavin-T (ThT). Endothelial cells were exposed to placental EVs overnight. Endothelial cell activation was measured by the quantification of cell-surface ICAM-1 using a cell-based ELISA. EVs from preeclamptic placentae carried significantly (p < 0.001) more misfolded proteins than normotensive controls. Incubating preeclamptic placental explants in the presence of melatonin (1 µM and 10 µM) significantly (p < 0.001) reduced the misfolded proteins carried by EVs. Culturing endothelial cells in the presence of preeclamptic EVs significantly increased the expression of ICAM-1. This increased ICAM-1 expression was significantly reduced when the endothelial cells were exposed to preeclamptic EVs cultured in the presence of melatonin. This study demonstrates that melatonin reduces the amount of misfolded proteins carried by EVs from preeclamptic placentae and reduces the ability of these EVs to activate endothelial cells. Our study provides further preclinical support for the use of melatonin as a treatment for preeclampsia.
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Mayeur, Sylvain, Steve Lancel, Nicolas Theys, Marie-Amélie Lukaszewski, Sophie Duban-Deweer, Bruno Bastide, Johan Hachani, et al. "Maternal calorie restriction modulates placental mitochondrial biogenesis and bioenergetic efficiency: putative involvement in fetoplacental growth defects in rats." American Journal of Physiology-Endocrinology and Metabolism 304, no. 1 (January 1, 2013): E14—E22. http://dx.doi.org/10.1152/ajpendo.00332.2012.
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Low birth weight is associated with an increased risk for developing type 2 diabetes and metabolic diseases. The placental capacity to supply nutrients and oxygen to the fetus represents the main determiner of fetal growth. However, few studies have investigated the effects of maternal diet on the placenta. We explored placental adaptive proteomic processes implicated in response to maternal undernutrition. Rat term placentas from 70% food-restricted (FR30) mothers were used for a proteomic screen. Placental mitochondrial functions were evaluated using molecular and functional approaches, and ATP production was measured. FR30 drastically reduced placental and fetal weights. FR30 placentas displayed 14 proteins that were differentially expressed, including several mitochondrial proteins. FR30 induced a marked increase in placental mtDNA content and changes in mitochondrial functions, including modulation of the expression of genes implicated in biogenesis and bioenergetic pathways. FR30 mitochondria showed higher oxygen consumption but failed to maintain their ATP production. Maternal undernutrition induces placental mitochondrial abnormalities. Although an increase in biogenesis and bioenergetic efficiency was noted, placental ATP level was reduced. Our data suggest that placental mitochondrial defects may be implicated in fetoplacental pathologies.
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Szenasi, Nikolett Lilla, Eszter Toth, Andrea Balogh, Kata Juhasz, Katalin Karaszi, Oliver Ozohanics, Zsolt Gelencser, et al. "Proteomic identification of membrane-associated placental protein 4 (MP4) as perlecan and characterization of its placental expression in normal and pathologic pregnancies." PeerJ 7 (June 20, 2019): e6982. http://dx.doi.org/10.7717/peerj.6982.
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BackgroundMore than 50 human placental proteins were isolated and physico-chemically characterized in the 70–80s by Hans Bohn and co-workers. Many of these proteins turned to have important role in placental functions and diagnostic significance in pregnancy complications. Among these proteins was membrane-associated placental protein 4 (MP4), for which identity or function has not been identified yet. Our aim was to analyze the sequence and placental expression of this protein in normal and complicated pregnancies including miscarriage, preeclampsia and HELLP syndrome.MethodsLyophilized MP4 protein and frozen healthy placental tissue were analyzed using HPLC-MS/MS. Placental tissue samples were obtained from women with elective termination of pregnancy (first trimester controls,n= 31), early pregnancy loss (EPL) (n= 13), early preeclampsia without HELLP syndrome (n= 7) and with HELLP syndrome (n= 8), late preeclampsia (n= 8), third trimester early controls (n= 5) and third trimester late controls (n= 9). Tissue microarrays were constructed from paraffin-embedded placentas (n= 81). Slides were immunostained with monoclonal perlecan antibody and evaluated using light microscopy and virtual microscopy. Perlecan was also analyzed for its expression in placentas from normal pregnancies using microarray data.ResultsMass spectrometry-based proteomics of MP4 resulted in the identification of basement membrane-specific heparan sulfate proteoglycan core protein also known as perlecan. Immunohistochemistry showed cytoplasmic perlecan localization in syncytiotrophoblast and cytotrophoblasts of the villi. Perlecan immunoscore decreased with gestational age in the placenta. Perlecan immunoscores were higher in EPL compared to controls. Perlecan immunoscores were higher in early preeclampsia without and with HELLP syndrome and lower in late preeclampsia than in respective controls. Among patients with preeclampsia, placental perlecan expression positively correlated with maternal vascular malperfusion and negatively correlated with placental weight.ConclusionOur findings suggest that an increased placental perlecan expression may be associated with hypoxic ischaemic injury of the placenta in miscarriages and in early preeclampsia with or without HELLP syndrome.
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Barreto, Rodrigo da Silva Nunes, Ana Claudia Oliveira Carreira, Mônica Duarte da Silva, Leticia Alves Fernandes, Rafaela Rodrigues Ribeiro, Gustavo Henrique Doná Rodrigues Almeida, Bruna Tassia dos Santos Pantoja, Milton Yutaka Nishiyama Junior, and Maria Angelica Miglino. "Mice Placental ECM Components May Provide A Three-Dimensional Placental Microenvironment." Bioengineering 10, no. 1 (December 22, 2022): 16. http://dx.doi.org/10.3390/bioengineering10010016.
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Bioethical limitations impair deeper studies in human placental physiology, then most studies use human term placentas or murine models. To overcome these challenges, new models have been proposed to mimetize the placental three-dimensional microenvironment. The placental extracellular matrix plays an essential role in several processes, being a part of the establishment of materno-fetal interaction. Regarding these aspects, this study aimed to investigate term mice placental ECM components, highlighting its collagenous and non-collagenous content, and proposing a potential three-dimensional model to mimetize the placental microenvironment. For that, 18.5-day-old mice placenta, both control and decellularized (n = 3 per group) were analyzed on Orbitrap Fusion Lumos spectrometer (ThermoScientific) and LFQ intensity generated on MaxQuant software. Proteomic analysis identified 2317 proteins. Using ECM and cell junction-related ontologies, 118 (5.1%) proteins were filtered. Control and decellularized conditions had no significant differential expression on 76 (64.4%) ECM and cell junction-related proteins. Enriched ontologies in the cellular component domain were related to cell junction, collagen and lipoprotein particles, biological process domain, cell adhesion, vasculature, proteolysis, ECM organization, and molecular function. Enriched pathways were clustered in cell adhesion and invasion, and labyrinthine vasculature regulation. These preserved ECM proteins are responsible for tissue stiffness and could support cell anchoring, modeling a three-dimensional structure that may allow placental microenvironment reconstruction.
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Grimaldi, Brooke, Hamid-Reza Kohan-Ghadr, and Sascha Drewlo. "The Potential for Placental Activation of PPARγ to Improve the Angiogenic Profile in Preeclampsia." Cells 11, no. 21 (November 6, 2022): 3514. http://dx.doi.org/10.3390/cells11213514.
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Preeclampsia (PE) is one of the most common causes of maternal-fetal morbidity and mortality world-wide. While the underlying causes of PE remain elusive, aberrant trophoblast differentiation and function are thought to cause an imbalance of secreted angiogenic proteins resulting in systemic endothelial dysfunction and organ damage in the mother. The placental dysfunction is also characterized by a reduction of the transcription factor, peroxisome proliferator activated receptor γ (PPARγ) which normally promotes trophoblast differentiation and healthy placental function. This study aimed to understand how placental activation of PPARγ effects the secretion of angiogenic proteins and subsequently endothelial function. To study this, healthy and PE placental tissues were cultured with or without the PPARγ agonist, Rosiglitazone, and a Luminex assay was performed to measure secreted proteins from the placenta. To assess the angiogenic effects of placental activation of PPARγ, human umbilical vein endothelial cells (HUVECs) were cultured with the placental conditioned media and the net angiogenic potential of these cells was measured by a tube formation assay. This is the first study to show PPARγ’s beneficial effect on the angiogenic profile in the human preeclamptic placenta through the reduction of anti-angiogenic angiopoietin-2 and soluble endoglin and the upregulation of pro-angiogenic placental growth factor, fibroblast growth factor-2, heparin-binding epidermal growth factor, and follistatin. The changes in the angiogenic profile were supported by the increased angiogenic potential observed in the HUVECs when cultured with conditioned media from rosiglitazone-treated preeclamptic placentas. The restoration of these disrupted pathways by activation of PPARγ in the preeclamptic placenta offers potential to improve placental and endothelial function in PE.
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Kumar K. V., Anil, Kavitha S., and Sreekanth K. S. "Regulatory proteins in placental angiogenesis." Biomedicine 41, no. 4 (December 31, 2021): 694–700. http://dx.doi.org/10.51248/.v41i4.944.
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The vasculature of the placenta plays a crucial role during the course of pregnancy in order to maintain the growing need of the fetus. Abnormal placental structure and function significantly increase the risk of stillbirth. Various growth factors and cytokines play an important role in the vasculogenesis and angiogenesis of placenta. These processes are stimulated by various pro-angiogenic factors. The activities of these factors are also stimulated by hypoxia. In some of the physiological phenomenon like ovulation, embryogenesis as well as in wound healing intense blood vessel growth can be seen similar to that seen in placenta. Therefore, factors that induce and maintain placental vascular growth and function are of considerable developmental and clinical significance. The total arterial architecture may also depend upon the pro-angiogenic factors. Hormones and other growth factors are other contributors of this vasculogenesis and angiogenesis. Any dysfunction of factors can lead to foetal hypoxia and related complications. This review describes the major growth factors and their significant role in vasculogenesis and angiogenesis of placenta.
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Avissar, N., C. Eisenmann, J. G. Breen, S. Horowitz, R. K. Miller, and H. J. Cohen. "Human placenta makes extracellular glutathione peroxidase and secretes it into maternal circulation." American Journal of Physiology-Endocrinology and Metabolism 267, no. 1 (July 1, 1994): E68—E76. http://dx.doi.org/10.1152/ajpendo.1994.267.1.e68.
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Extracellular glutathione peroxidase (eGPX) is a selenoglycoprotein distinct from cellular glutathione peroxidase (cGPX). The cDNA for eGPX has recently been cloned from human placenta. To determine whether human placenta makes both cGPX and eGPX and secretes eGPX, we used specific immunoprecipitations of 75Se metabolically labeled proteins from full-term placental explants in culture and perfused placental lobules. Placental explants and metabolically active, dually perfused placental lobules synthesized and contained both cGPX and eGPX and secreted eGPX. Perfused tissue secreted eGPX into the maternal but not into the fetal perfusate. In situ hybridizations using antisense and sense eGPX riboprobes were performed on sections of first-, second-, and third-trimester placentas. In the first-trimester placenta, transcripts were localized predominantly to cytotrophoblast cells, whereas in the full-term placenta syncytiotrophoblast cells and stromal cells but not fetal endothelial cells expressed eGPX mRNA. It is concluded that human placenta synthesizes both cGPX and eGPX and secretes eGPX into the maternal circulation, consistent with the location of the eGPX mRNA.
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Tissot van Patot, M. C., J. Bendrick-Peart, V. E. Beckey, N. Serkova, and L. Zwerdlinger. "Greater vascularity, lowered HIF-1/DNA binding, and elevated GSH as markers of adaptation to in vivo chronic hypoxia." American Journal of Physiology-Lung Cellular and Molecular Physiology 287, no. 3 (September 2004): L525—L532. http://dx.doi.org/10.1152/ajplung.00203.2003.
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Vascularity is increased in placentas from high- compared with low-altitude pregnancies. An angiogenic response to hypoxia may protect an organ from further hypoxic insult by increasing blood flow and oxygen delivery to the tissue. We hypothesized that increased placental vascularity is sufficient to adapt to high altitude. Therefore, indexes of hypoxic stress would not be present in placentas from successful high-altitude pregnancies. Full-thickness placental biopsies were 1) collected and frozen in liquid nitrogen within 5 min of placental delivery and 2) fixed in formalin for stereologic analyses at high (3,100 m, n = 10) and low (1,600 m, n = 10) altitude. Hypoxia-inducible transcription factor (HIF-1) activity was analyzed by ELISA. Western blot analyses were used to evaluate HIF-1α, HIF-1β, HIF-2α, von Hippel-Lindau protein, VEGF, Flt-1, enolase, and GAPDH. Magnetic resonance spectroscopy was used to evaluate endogenous metabolism. The ratio of placental capillary surface density to villous surface density was 70% greater at high compared with low altitude. HIF-1 activity and HIF-1-associated proteins were unchanged in placentas from high- vs. low-altitude pregnancies. Placental expression of HIF-1-mediated proteins VEGF, Flt-1, enolase, and GAPDH were unchanged at high vs. low altitude. Succinate, GSH, phosphomonoesters, and ADP were elevated in placenta from high compared with low altitude. Placentas from uncomplicated high-altitude pregnancies have greater vascularity and no indication of significant hypoxic stress at term compared with placentas from low altitude.
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Karteris, E., D. Grammatopoulos, H. Randeva, and E. W. Hillhouse. "Signal Transduction Characteristics of the Corticotropin-Releasing Hormone Receptors in the Feto-Placental Unit." Journal of Clinical Endocrinology & Metabolism 85, no. 5 (May 1, 2000): 1989–96. http://dx.doi.org/10.1210/jcem.85.5.6590.
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Abstract Placentally derived CRH plays a major role in the mechanisms controlling human pregnancy and parturition. In this study, we sought to investigate the signal transduction mechanisms of CRH Type-1 receptors in the feto-placental unit. To clarify the signal transduction components in placenta and fetal membranes, we investigated the expression of G proteins and adenylate cyclase. Using the nonhydrolysable photoreactive analog [α-32P] GTP-azidoanilide and peptide antisera raised against G proteinα -subunits, we studied coupling of CRH receptors to G proteins in both placental and fetal membranes. Treatment of placental membranes with human CRH (100 nm) increased the labeling of Gq, Go, and Gz but not Gi and Gs. Treatment of fetal membranes with human CRH (100 nm) increased the labeling of Go and Gq but not Gi, Gs, and Gz. These results were supported by experiments that showed that CRH failed to activate adenylate cyclase in these tissues, but induced an increase in inositol phosphates instead. These findings provide new insights into the components of the signal transduction machinery in both fetal and placental membranes and suggest that CRH Type-1 receptors can couple to different G proteins in different tissues. The physiological significance of these observations remains to be elucidated.
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Selvaratnam, Johanna, Haiyan Guan, James Koropatnick, and Kaiping Yang. "Metallothionein-I- and -II-deficient mice display increased susceptibility to cadmium-induced fetal growth restriction." American Journal of Physiology-Endocrinology and Metabolism 305, no. 6 (September 15, 2013): E727—E735. http://dx.doi.org/10.1152/ajpendo.00157.2013.
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Maternal cadmium exposure induces fetal growth restriction (FGR), but the underlying mechanisms remain largely unknown. The placenta is the main organ known to protect the fetus from environmental toxins such as cadmium. In this study, we examine the role of the two key placental factors in cadmium-induced FGR. The first is placental enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is known to protect the fetus from exposure to high cortisol levels and subsequently FGR, and the second the cadmium binding/sequestering proteins metallotheionein (MT)-I and -II. Using the MT-I/II −/− mouse model, pregnant mice were administered cadmium, following which pups and placentas were collected and examined. MT-I/II−/− pups exposed to cadmium were significantly growth restricted, but neither placental weight nor 11β-HSD2 was altered. Although cadmium administration did not result in any visible structural changes in the placenta, increased apoptosis was detected in MT-I/II−/− placentas following cadmium exposure, with a significant increase in levels of both p53 and caspase 3 proteins. Additionally, glucose transporter (GLUT1) was significantly reduced in MT-I/II−/− placentas of pups exposed to cadmium, whereas zinc transporter (ZnT-1) remained unaltered. Taken together, these results demonstrate that MT-I/II−/− mice are more vulnerable to cadmium-induced FGR. The present data also suggest that increased apoptosis and reduced GLUT1 expression in the placenta contribute to the molecular mechanisms underlying cadmium-induced FGR.
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Kingdom, John, Ian Mackie, Stephen Burrell, Siobhán Quenby, Eric Jauniaux, Samuel Machin, and Siobhán Donohoe. "Ontogeny of Beta 2 Glycoprotein I and Annexin V in Villous Placenta of Normal and Antiphospholipid Syndrome Pregnancies." Thrombosis and Haemostasis 84, no. 07 (2000): 32–38. http://dx.doi.org/10.1055/s-0037-1613963.
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Summaryβ2-glycoprotein I (β2GPI) and annexin V (AV) have been implicated in the pathophysiology of the antiphospholipid syndrome (APS). We investigated their placental expression in normal villous tissues throughout gestation; first trimester n = 10, early second trimester; n = 4, preterm; n = 5) and term; n = 7 and in APS (2 first trimester, 1 preterm and 8 term deliveries). β2GPI and AV were both expressed by the placenta from as early as seven weeks gestation and were colocalised to the syncytiotrophoblast. β2GPI staining was also observed in stromal cells, being present in phagocytic Hofbauer cells and surrounding newly formed fetal vessels in a perivascular pattern, from seven to seventeen weeks gestation. An abnormal morphological distribution of AV was noted in one first trimester APS placenta, and for β2GPI in a further first trimester placenta. When placental proteins were extracted from villous tissue, the concentration of AV/mg protein in term APS placentas (median, interquartile range) (aPS; 8.16, 7.87-9.72 µg/mg) was significantly higher (p <0.005) than normal term levels (normal; 2.47, 2.28-2.54 µg/mg). β2GPI increased with advancing gestation (first trimester; 0.93, 0.64-1.26 µg/mg, term; 3.67, 2.58-4.48 µg/mg) in normal pregnancy. Term APS placentas had a reduced β2GPI content (2.31, 1.87-2.49 µg/mg), p <0.05. The placental role of these proteins remains to be identified.
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Schaiff, W. Timothy, F. F. (Russ) Knapp, Yaacov Barak, Tal Biron-Shental, D. Michael Nelson, and Yoel Sadovsky. "Ligand-Activated Peroxisome Proliferator Activated Receptor γ Alters Placental Morphology and Placental Fatty Acid Uptake in Mice." Endocrinology 148, no. 8 (August 1, 2007): 3625–34. http://dx.doi.org/10.1210/en.2007-0211.
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The nuclear receptor peroxisome proliferator activated receptor γ (PPARγ) is essential for murine placental development. We previously showed that activation of PPARγ in primary human trophoblasts enhances the uptake of fatty acids and alters the expression of several proteins associated with fatty acid trafficking. In this study we examined the effect of ligand-activated PPARγ on placental development and transplacental fatty acid transport in wild-type (wt) and PPARγ+/− embryos. We found that exposure of pregnant mice to the PPARγ agonist rosiglitazone for 8 d (embryonic d 10.5–18.5) reduced the weights of wt, but not PPARγ+/− placentas and embryos. Exposure to rosiglitazone reduced the thickness of the spongiotrophoblast layer and the surface area of labyrinthine vasculature, and altered expression of proteins implicated in placental development. The expression of fatty acid transport protein 1 (FATP1), FATP4, adipose differentiation related protein, S3-12, and myocardial lipid droplet protein was enhanced in placentas of rosiglitazone-treated wt embryos, whereas the expression of FATP-2, -3, and -6 was decreased. Additionally, rosiglitazone treatment was associated with enhanced accumulation of the fatty acid analog 15-(p-iodophenyl)-3-(R, S)-methyl pentadecanoic acid in the placenta, but not in the embryos. These results demonstrate that in vivo activation of PPARγ modulates placental morphology and fatty acid accumulation.
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McKinnon, Brett, Huika Li, Kerry Richard, and Robin Mortimer. "Synthesis of Thyroid Hormone Binding Proteins Transthyretin and Albumin by Human Trophoblast." Journal of Clinical Endocrinology & Metabolism 90, no. 12 (December 1, 2005): 6714–20. http://dx.doi.org/10.1210/jc.2005-0696.
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Context: Mechanisms regulating materno-fetal transfer of thyroid hormone are not well understood. Modulation of trophoblast type 3 iodothyronine deiodinase (D3) may play an important role. Objective: The objective of this study was to investigate trophoblast thyroid hormone binding proteins that may modulate interactions between D3 and T4. Design: Placentas were obtained by informed consent from women delivering normal infants by repeat cesarean section at 38–40 wk gestation. T4 and T3 binding was examined in human placenta. Serum thyroid hormone binding proteins were identified by Western blotting, and their mRNA was examined by RT-PCR. Presence of these proteins in trophoblast was determined by immunocytochemistry and immunofluorescence. Cytosol was progressively purified to reveal additional thyroid hormone binding proteins that were identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry. Effects of mefenamic acid on placental deiodination were examined by HPLC. Results: We detected high-affinity T4 and T3 binding in human placental cytosol. All three major serum-binding proteins, T4 binding globulin (TBG), transthyretin (TTR), and albumin, were present in cytosol. TTR mRNA and albumin mRNA were detected in human placenta, and TTR and albumin were identified histochemically in syncytiotrophoblasts. Neither TBG mRNA nor TBG was detected, suggesting that plasma TBG had contaminated the cytosol preparation. Low-affinity thyroid hormone binding proteins α-1-antitrypsin and α-1-acid glycoprotein were also identified. Addition of mefenamic acid, a potent inhibitor of thyroid hormone binding, to placental cytosol significantly enhanced deiodination of T4 by D3. Conclusions: Placenta produces a series of thyroid hormone binding proteins that may modify thyroid hormone deiodination and materno-fetal thyroid hormone transport.
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Borges-Vélez, Gabriel, Juan A. Arroyo, Yadira M. Cantres-Rosario, Ana Rodriguez de Jesus, Abiel Roche-Lima, Julio Rosado-Philippi, Lester J. Rosario-Rodríguez, María S. Correa-Rivas, Maribel Campos-Rivera, and Loyda M. Meléndez. "Decreased CSTB, RAGE, and Axl Receptor Are Associated with Zika Infection in the Human Placenta." Cells 11, no. 22 (November 16, 2022): 3627. http://dx.doi.org/10.3390/cells11223627.
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Zika virus (ZIKV) compromises placental integrity, infecting the fetus. However, the mechanisms associated with ZIKV penetration into the placenta leading to fetal infection are unknown. Cystatin B (CSTB), the receptor for advanced glycation end products (RAGE), and tyrosine-protein kinase receptor UFO (AXL) have been implicated in ZIKV infection and inflammation. This work investigates CSTB, RAGE, and AXL receptor expression and activation pathways in ZIKV-infected placental tissues at term. The hypothesis is that there is overexpression of CSTB and increased inflammation affecting RAGE and AXL receptor expression in ZIKV-infected placentas. Pathological analyses of 22 placentas were performed to determine changes caused by ZIKV infection. Quantitative proteomics, immunofluorescence, and western blot were performed to analyze proteins and pathways affected by ZIKV infection in frozen placentas. The pathological analysis confirmed decreased size of capillaries, hyperplasia of Hofbauer cells, disruption in the trophoblast layer, cell agglutination, and ZIKV localization to the trophoblast layer. In addition, there was a significant decrease in CSTB, RAGE, and AXL expression and upregulation of caspase 1, tubulin beta, and heat shock protein 27. Modulation of these proteins and activation of inflammasome and pyroptosis pathways suggest targets for modulation of ZIKV infection in the placenta.
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Anderson, T. D., N. F. Cheville, and V. P. Meador. "Pathogenesis of Placentitis in the Goat Inoculated with Brucella abortus. II. Ultrastructural Studies." Veterinary Pathology 23, no. 3 (May 1986): 227–39. http://dx.doi.org/10.1177/030098588602300302.
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Pregnant goats were inoculated intravenously or in uterine arteries with Brucella abortus, and tissues from the uterus and placenta were examined by electron microscopy. Identification of B. abortus in placentae was with antibody-coated colloidal gold. B. abortus was first seen in phagosomes of erythrophagocytic trophoblasts and in the rough endoplasmic reticulum of chorioallantoic trophoblasts. Subsequently, trophoblast necrosis and ulceration of chorioallantoic membranes were present. Coincidently, B. abortus was present in the lumen of placental capillaries. In late stages of infection, placental vasculitis was present, and placentomal trophoblasts were separated from maternal syncytial epithelium. In lesions with vasculitis, large numbers of B. abortus were in connective tissue of chorionic villi. Within the placentome, trophoblasts that lined chorionic villi contained no intracellular bacteria and were separated from B. abortus by intact basement membranes. These results suggest that bacteremic B. abortus is endocytosed by erythrophagocytic trophoblasts and that B. abortus replicates in the rough endoplasmic reticulum of chorioallantoic trophoblasts. Replication of brucellae in trophoblastic rough endoplasmic reticulum is unique; we believe that B. abortus may utilize endoplasmic reticulum for synthesis and glycosylation of bacterial membrane proteins or that B. abortus catabolizes trophoblast secretory proteins.
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Weber, Milena, Ivona Baričević-Jones, Romana Masnikosa, Dejan Filimonović, Željko Miković, and Olgica Nedić. "Receptors and Binding Proteins for Insulin and Insulin-Like Growth Factors in the Placenta of Healthy Mothers and Mothers with Insulin-Dependent Diabetes Mellitus." Journal of Medical Biochemistry 28, no. 1 (January 1, 2009): 30–35. http://dx.doi.org/10.2478/v10011-008-0030-3.
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Receptors and Binding Proteins for Insulin and Insulin-Like Growth Factors in the Placenta of Healthy Mothers and Mothers with Insulin-Dependent Diabetes Mellitus The IGF system of human placenta consists of insulin-like growth factors (IGF)-I and -II, their receptors (IGF-1R and IGF-2R), and binding proteins (IGFBP-1 to -6). Due to many structural and metabolic similarities with insulin, the IGF system cannot be examined separately from insulin and its receptor (IR). In this study gel filtration was used to detect solubilized membrane proteins of the placenta obtained from healthy mothers and mothers with IDDM. In order to detect placental membrane proteins that bind IGF molecules (and insulin), the solubilized membranes were incubated with each of the three 125I-labelled ligands: 125I-IGF-I, 125I-IGF-II and 125I-insulin prior to gel filtration chromatography. The biochemical evidence of the presence of receptors for insulin and IGFs, as well as that of IGFBP-1 were obtained by immunoblotting. Herein we demonstrated that, considering IGF and insulin receptor content, the placental tissue obtained from mothers with IDDM was not different from that obtained from healthy mothers. However, the concentration of IGFBP-1 differed between the examined placentas. IDDM in mothers caused an increase in the amount of IGFBP-1 in their placentas and, consequently, the amount of the labelled ligand bound to it. The redistribution of IGFs between the receptors and IGFBP-1 may be involved in regulatory mechanisms in the placenta of mothers with IDDM.
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Li, Ji-Wei, Jian Hu, Ming Wei, Ying-Ying Guo, and Pei-Shi Yan. "The Effects of Maternal Obesity on Porcine Placental Efficiency and Proteome." Animals 9, no. 8 (August 12, 2019): 546. http://dx.doi.org/10.3390/ani9080546.
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Maternal obesity is associated with impaired maternal metabolism and affects the developmental programming of the fetus. The placenta is dysfunctional when exposed to an obese intrauterine environment and can transduce and mediate detrimental maternal impacts to the fetus through mechanisms that remain largely unknown. The main objective of this study was to investigate the effects of maternal obesity on the porcine placental proteome and to analyze the deregulated proteins and potential pathways predicted to be disturbed in obese placentas, using sows with high backfat as a model of obese pregnancy. The sows were divided into two groups based on their backfat thickness: normal backfat (NBF, 17–22 mm; n = 30) and high backfat (HBF, ≥23 mm; n = 30) as the maternal obesity group. The placental tissues used for the proteomic and biochemical analyses were obtained through vaginal delivery, and the maternal blood samples used to determine the metabolic parameters were collected at day 107 of pregnancy. Our study demonstrated that HBF sows had significantly decreased placental efficiency, increased plasma-free fatty acids and triglyceride levels, and increased proinflammatory cytokines plasma levels (p < 0.05). HBF placentas had significantly higher malondialdehyde level, lower total antioxidant capacity and antioxidase activity, increased triglyceride content and enhanced proinflammatory tumor necrosis factor- α (TNF-α) and interleukin-6 (IL-6) contents (p < 0.05). Among the 4652 proteins identified using the proteomic method, 343 were quantified as differentially abundant proteins, which were involved in many vital biological processes. Based on our bioinformatic and placental biochemical analyses, we concluded that maternal obesity is associated with abnormal carbohydrate and lipid metabolism, mitochondrial dysfunction, decreased steroid hormone biosynthesis, and increased oxidative stress and inflammation in the placenta. The results of this study are undoubtedly valuable to other researchers.
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Mark, P. J., J. L. Lewis, M. L. Jones, and B. J. Waddell. "158. THE UNFOLDED PROTEIN RESPONSE MAY CONTRIBUTE TO GLUCOCORTICOID-INDUCED PLACENTAL GROWTH RESTRICTION IN THE RAT VIA INCREASED PLACENTAL EXPRESSION OF HEAT SHOCK PROTEIN 70." Reproduction, Fertility and Development 22, no. 9 (2010): 76. http://dx.doi.org/10.1071/srb10abs158.
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Perturbations of normal endoplasmic reticulum (ER) physiology occur in a number of pathological conditions, including diabetes and preeclampsia. These pathologies are associated with elevated levels of inappropriately folded proteins and induction of ER stress. Accumulation of misfolded proteins induces the unfolded protein response which increases ER protein folding capacity and promotes ER-associated degradation of unfolded proteins. Glucocorticoids are essential for maturation of fetal organs, however excess exposure during pregnancy retards fetal and placental growth. Glucocorticoids also induce ER stress within macrophages, which reside within the placenta, and activate immune responses which can lead to oxidative stress and subsequent placental dysfunction. We hypothesised that excess glucocorticoid exposure would induce ER stress within the placenta and contribute to restriction of fetal and placental growth. This study compared placentas (n = 6/group) for control (Con) and dexamethasone-exposed pregnancies (Dex; 0.75 μg/mL drinking water from day 13 of gestation) at days 16 and 22 of gestation in the rat (term = 23 days). Placentas were dissected into junctional (JZ) and labyrinth (LZ) zones for separate analysis. Quantitative PCR was used to determine expression of mRNA for markers of ER stress, including heat shock factors (HSF-1 and HSF-2), heat shock proteins (HSP-70 and HSP-90) and C/EBP homologous protein (CHOP10). HSF-1 expression increased 2- to 4-fold from day 16 to 22 in both placental zones, but was not increased by glucocorticoids. Dex-exposure increased HSP-70 expression 2- to 3-fold in the LZ at both days of gestation, indicative of an ER stress response. Similar patterns for JZ expression of HSP-70 were observed. JZ expression of HSP-90 was also upregulated by Dex at day 22 but not day 16. CHOP10 was not induced by Dex-administration in either zone at either gestational time, which suggests that rather than activation of the ATF6/PERK pathway, the activation of ER stress is likely to be via XBP1 induction.
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Sun, Luming, Jia Zhou, Kai Wang, Jian Wang, Ling Shang, Jianguang Zhang, Junqing Wu, and David S. Cram. "Placental Up-Regulation of Leptin and ARMS2 is Associated with Growth Discordance in Monochorionic Diamniotic Twin Pregnancies." Twin Research and Human Genetics 20, no. 2 (March 17, 2017): 169–79. http://dx.doi.org/10.1017/thg.2017.11.
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Fetal growth discordance is a relatively common complication of monochorionic diamniotic (MCDA) twin pregnancies and is caused by a combination of maternal and placental factors. The aim of the study was to survey placental gene expression patterns and identify genes associated with growth discordance. Clinical samples comprised eight growth-discordant MCDA twin placentas (31+3–34+4 weeks gestational age) and six growth-concordant twin placentas (31+2–37 weeks gestational age). Gene expression libraries were constructed from placental biopsy samples and analyzed by RNA-sequencing. The distribution and relative abundance of mRNA transcripts expressed in the smaller and larger placentas from growth-discordant and concordant MCDA twins was remarkably similar. However, leptin (LEP) and age-related maculopathy susceptibility 2 (ARMS2) mRNA levels were exclusively up-regulated in all of the eight smaller growth-discordant twin placentas. Quantitative real-time PCR of independent biopsy samples confirmed the levels of differential mRNA expression for both genes. Immunohistochemical analysis of tissue sections from matching twin placentas showed increased leptin expression in 5–10% of blood vessel cells of the smaller placenta and marginally higher levels of ARMS2 expression in the microvillous membrane of the smaller placenta. Based on these findings, we speculate that up-regulation of leptin and ARMS2 forms part of an important survival mechanism to compensate for placental growth discordance. Since, leptin and ARMS2 are both expressed as soluble proteins, they may have clinical potential as measurable biomarkers for predicting the onset of growth discordance in MCDA twin pregnancies.
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Hay, WW. "Regulation of placental metabolism by glucose supply." Reproduction, Fertility and Development 7, no. 3 (1995): 365. http://dx.doi.org/10.1071/rd9950365.
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Glucose is supplied to the placenta and fetus from the maternal plasma according to concentration-dependent mechanisms exhibiting saturation kinetics that are mediated by facilitative transporter proteins on both the maternal-facing microvillus and fetal-facing basal trophoblast membranes. Placental glucose transport to the fetus requires a net maternal-to-fetal plasma glucose concentration gradient that is determined by placental as well as fetal glucose consumption. Fetal plasma glucose concentration, independent of maternal glucose concentration, regulates the partition of placental glucose uptake into transfer to the fetus and consumption by the placenta. Placental transport capacity increases with advancing gestation, probably by an increased number of transporter proteins as surface area increases. Placental glucose consumption contributes to most or all of placental lactate and fructose production and other less well defined non-oxidative pathways of carbon metabolism. Placental glucose consumption accounts for at least 50% of placental oxygen consumption which remains independent of short-term or long-term changes in placental glucose supply, thus requiring varying amounts of other carbon substrates. Placental glucose supply, therefore, plays a key role in regulating placental glucose metabolism and placental carbon balance, and interacts reciprocally with other carbon substrates to maintain placental oxidative metabolism.
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Ziegert, M., S. S. Witkin, I. Sziller, H. Alexander, E. Brylla, and W. Härtig. "Heat Shock Proteins and Heat Shock Protein-Antibody Complexes in Placental Tissues." Infectious Diseases in Obstetrics and Gynecology 7, no. 4 (1999): 180–85. http://dx.doi.org/10.1155/s1064744999000307.
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Objective:The relationship between pregnancy outcome and expression of the heat shock proteins (hsps) or hsp-antibody complexes of 60kD (hsp60), 70kD (hsp70), and 90kD (hsp90) in placental tissue and circulating antibodies to hsps was evaluated.Method:Expression of hsp60, hsp70, and hsp90 in placentae from 12 women with preterm birth, eight with intrauterine growth restriction (IUGR), and 10 with term birth, as well as the presence of the corresponding antibodies, was investigated by a new carbocyanine double fluorescence technique. Results were compared with microbiological findings and circulating antibodies to hsps in sera.Results:In each placental specimen examined, hsp60, hsp70, and hsp90 were identified. However, hsp70-antibody complexes were detected in only four of the preterm labor cases. Similarly, hsp60-antibody complexes were detected in only five preterm labor patients and in one patient with IUGR. None of the placentae contained hsp90-antibody complexes. In the preterm birth group, all patients with hsp60-antibody complexes were also positive for circulating antibodies to hsp60. The presence of hsp70-antibody complexes also correlated with hsp70 antibody in sera.Conclusions:Formation of hsp60- and hsp70-antibody complexes in the placenta may contribute to the induction of preterm birth. Women sensitized to these antibodies may be at increased risk for adverse pregnancy outcome. Infect. Dis. Obstet. Gynecol. 7:180–185, 1999.
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Stenhouse, Claire, Katherine M. Halloran, Makenzie G. Newton, Dana Gaddy, Larry J. Suva, and Fuller W. Bazer. "Novel mineral regulatory pathways in ovine pregnancy: II. Calcium-binding proteins, calcium transporters, and vitamin D signaling." Biology of Reproduction 105, no. 1 (April 5, 2021): 232–43. http://dx.doi.org/10.1093/biolre/ioab063.
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Abstract Mineralization of the fetal mammalian skeleton requires a hypercalcemic gradient across the placenta from mother to fetus. However, the mechanisms responsible for maintaining the placental transport of calcium remain poorly understood. This study aimed to identify calcium and vitamin D regulatory pathway components in ovine endometria and placentae across gestation. Suffolk ewes were bred with fertile rams upon detection of estrus (Day 0). On Days 9, 12, 17, 30, 70, 90, 110, and 125 of pregnancy (n=3–14/Day), ewes were euthanized and hysterectomized. Calcium abundance was influenced by gestational day in uterine flushings and allantoic fluid (P<0.05). The expression of S100G, S100A9, S100A12, ATP2B3, ATP2B4, TRPV5, TRPV6, CYP11A1, CYP2R1, CYP24, and VDR mRNAs known to be involved in calcium binding, calcium transport, and vitamin D metabolism were quantified by qPCR. Mediators of calcium and vitamin D signaling were expressed by Day 17 conceptus tissue, and endometria and placentae across gestation. Gestational day influenced the expression of S100G, S100A9, S100A12, TRPV6, VDR, and CYP24 mRNAs in endometria and placentae (P<0.05). Gestational day influenced endometrial expression of ATP2B3, and placental expression of TRPV5, ATP2B4, and CYP11A1 (P<0.05). VDR protein localized to the endoderm and trophectoderm (Day 17 conceptus) and was expressed in endometria and placentae throughout gestation. The observed spatiotemporal profile suggests a potential role of calcium and vitamin D in the establishment of pregnancy and regulation of fetal and placental growth, providing a platform for further mechanistic investigation.
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Rampon, Christine, Stéphanie Bouillot, Adriana Climescu-Haulica, Marie-Hélène Prandini, Francine Cand, Yves Vandenbrouck, and Philippe Huber. "Protocadherin 12 deficiency alters morphogenesis and transcriptional profile of the placenta." Physiological Genomics 34, no. 2 (July 2008): 193–204. http://dx.doi.org/10.1152/physiolgenomics.00220.2007.
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Protocadherins are transmembrane proteins exhibiting homophilic adhesive activities through their extracellular domain. Protocadherin 12 ( Pcdh12) is expressed in angiogenic endothelial cells, mesangial cells of kidney glomeruli, and glycogen cells of the mouse placenta. To get insight into the role of this protein in vivo, we analyzed PCDH12-deficient mice and investigated their placental phenotype. The mice were alive and fertile; however, placental and embryonic sizes were reduced compared with wild-type mice. We observed defects in placental layer segregation and a decreased vascularization of the labyrinth associated with a reduction in cell density in this layer. To understand the molecular events responsible for the phenotypic alterations observed in Pcdh12−/− placentas, we analyzed the expression profile of embryonic day 12.5 mutant placentas compared with wild-type placentas, using pangenomic chips: 2,289 genes exhibited statistically significant changes in expressed levels due to loss of PCDH12. Functional grouping of modified genes was obtained by GoMiner software. Gene clusters that contained most of the differentially expressed genes were those involved in tissue morphogenesis and development, angiogenesis, cell-matrix adhesion and migration, immune response, and chromatin remodeling. Our data show that loss of PCDH12 leads to morphological alterations of the placenta and to notable changes in its gene expression profile. Specific genes emerging from the microarray screen support the biological modifications observed in PCDH12-deficient placentas.
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Kim, H. R., J. K. Kang, J. T. Yoon, H. H. Seong, C. S. Park, and D. I. Jin. "46DIFFERENTIAL PATTERNS OF PROTEIN SYNTHESIS BETWEEN NORMAL AND CLONED PLACENTAE." Reproduction, Fertility and Development 16, no. 2 (2004): 145. http://dx.doi.org/10.1071/rdv16n1ab46.
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Practical application of animal cloning by somatic cell nuclear transfer (SCNT) has been hampered by extremely low success rate. Most clones die before birth and survivors frequently display abnormalities. It is speculated that epigenetic reprogramming is somehow defective in reconstituted embryos (Reik W et al., 2003 Theriogenology 59 21–32; Han YM et al., 2003 Theriogenology 59, 33–44). It is likely that placental anomalies are directly or indirectly responsible for the death of cloned fetus and neonates. To address this question, we analyzed protein patterns of two placentae obtained after postnatal death of fetuses from SCNT of Korean Native Cattle and two normal placentae obtained after birth of AI fetuses. Global proteomics approach was employed by using 2-D gel electrophoresis and mass spectrometry to separate the different placenta proteins. Proteins within an isoelectric point range of 4.0 to 7.0 and a molecular weight range of 20–100kDa were analyzed by means of 2-D gel electrophoresis with three replications of each sample. The stained gels were scanned and calibrated at an optical resolution of 63.5μm/pixel using a GS-710 (Bio-Rad Laboratories, Hercules, CA, USA). Approximately 480 spots were detected in placental 2-D gel stained with coomassie-blue. Then, image analysis by Malanie III (Swiss Institute for Bioinformatics, Geneva, Switzerland) was performed to detect variations in protein spots between normal and SCNT placentae. In the comparison of normal and SCNT samples, at least 15 protein spots were identified as regulated differentially. Using MALDI-TOF-MS (PerSeptive Biosystems, Framinham, MA, USA), 10 spots were identified as up-regulated proteins in SCNT placentae including BPLP-I, Rho GDI 2, osteoclast stimulating factors, SM22, 60S Acidic Ribosomal and Protein P2, whereas five spots were down-regulated proteins such as Peroxiredoxin 2. Mass spectrometry with sequencing was used to further analyze the uncharacterized proteins. Most identified proteins in this analysis appeared to be related to cell proliferation and differentiation, fetal growth and development or metabolism. Further, specific functions of proteins in placenta have been investigated at the molecular levels during pregnancy.
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Taher, Shèdy, Yamilette Borja, Lucía Cabanela, Vincent J. Costers, Morgan Carson-Marino, Julie C. Bailes, Biswadeep Dhar, et al. "Cholecystokinin, gastrin, cholecystokinin/gastrin receptors, and bitter taste receptor TAS2R14: trophoblast expression and signaling." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 316, no. 5 (May 1, 2019): R628—R639. http://dx.doi.org/10.1152/ajpregu.00153.2018.
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We investigated expression of cholecystokinin (CCK) in humans and mice, and the bitter taste receptor TAS2R14 in the human placenta. Because CCK and gastrin activate the CCKBR receptor, we also explored placental gastrin expression. Finally, we investigated calcium signaling by CCK and TAS2R14. By RT-PCR, we found CCK/Cck and GAST/Gast mRNA expression in both normal human and mouse placentas, as well as in human trophoblast cell lines (TCL). Although both Cckar and – br mRNA were expressed in the mouse placenta, only CCKBR mRNA was detected in the human placenta and TCL. mRNA expression for TAS2R14 was also observed in the human placenta and TCL. Using immunohistochemistry, CCK protein was localized to the syncytiotrophoblast (ST) and extravillous trophoblast (EVT) in the human term placenta, and to trophoblast glycogen cells in mouse and human placentas. Gastrin and TAS2R14 proteins were also observed in ST and EVT of the human placenta. Both sulfated and nonsulfated CCK elicited a comparable rise in intracellular calcium in TCL, consistent with CCKBR expression. Three TAS2R14 agonists, flufenamic acid, chlorhexidine, and diphenhydramine, also evoked rises in intracellular calcium in TCL. These results establish CCK, gastrin, and their receptor(s) in both human and mouse placentas, and TAS2R14 in the human placenta. Both CCK and TAS2R14 agonists increased intracellular calcium in human TCL. Although the roles of these ligands and receptors, and their potential cross talk in normal and pathological placentas, are currently unknown, this study opens new avenues for placental research.
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Levy, RA, E. Avvad, J. Oliveira, and LC Porto. "Placental pathology in antiphospholipid syndrome." Lupus 7, no. 2_suppl (February 1998): 81–85. http://dx.doi.org/10.1177/096120339800700218.
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One of the major targets of antiphospholipid antibodies (aPL) is the placenta, the evolution of which during pregnancy has been well documented. Histopathological findings are related to gestational age, and several physiologic and pathologic alterations that occur during its development. The major findings in placentae from aPL positive patients are thrombosis, acute atherosis, a decreased number of syncytio-vascular membranes, increased number of syncytial knots and obliterative arteriopathy. These findings are not specific to the antiphospholipid syndrome (APS) and sometimes do not correlate with the fetal outcome. Histopathological study of placentae may elucidate mechanisms of action of aPL in fetal loss and other obstetric complications. In addition, it may assist in the investigation of the differential diagnosis between APS and pregnancy-induced hypertension. Immunohistochemical studies of local placental proteins contribute to this differential diagnosis.
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Bartho, Lucy A., Joshua J. Fisher, Sarah L. Walton, Anthony V. Perkins, and James S. M. Cuffe. "The effect of gestational age on mitochondrial properties of the mouse placenta." Reproduction and Fertility 3, no. 1 (February 1, 2022): 19–29. http://dx.doi.org/10.1530/raf-21-0064.
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Mitochondria are organelles within the cell that generate energy, which is essential to the developing placenta. As the placenta approaches term, organelles such as mitochondria and the endoplasmic reticulum adapt to cellular stressors (e.g. oxidative stress and fluctuations in oxygen concentration) which are likely to result in the progressive decline of tissue function, known as placental ageing. This ageing phenotype may induce cellular senescence, a process whereby the cell is no longer proliferating, yet remains metabolically active. Mitochondria, endoplasmic reticulum and senescent processes are still poorly understood in the developing placenta. Therefore, a rodent ontogeny model was used to measure genes and proteins involved in mitochondrial biogenesis, antioxidant function, electron transport chain, mitophagy, dynamics and unfolded protein response in the placenta. CD-1 mouse placental samples were collected at embryonic day (E)12.5, E14.5, E16.5 and E18.5 of pregnancy for gene and protein analysis via qPCR, protein assays and Western blotting. Mitochondrial content, SDHB (complex II) and MFN2 (mitochondrial fusion) proteins were all increased throughout pregnancy, while citrate synthase activity/mitochondrial content, Tfam, Sirt3, Mfn1, TOMM20 (mitochondrial biogenesis and dynamics); Tp53(senescence); Eif2ak3, Eif4g1(endoplasmic reticulum stress);NDUFB8, UQCRC2, ATP5A (electron transport chain sub-complexes) were decreased at E18.5, compared to E12.5. Overall, mitochondria undergo changes in response to gestational progression and pathways associated with cellular ageing to facilitate adaptions in a healthy pregnancy. This data holds great promise that mitochondrial markers across pregnancy may help to establish when a placenta is ageing inappropriately. Lay summary Human pregnancy lasts approximately 266 days. If a baby is born early, organs may be poorly formed but if pregnancy continues past this time, stillbirth risk is increased. Gestational duration is regulated by the placenta. As the placenta approaches the end of pregnancy, it displays properties similar to tissues from aged individuals. However, it is unknown how this placental ageing contributes to pregnancy duration. This study characterised normal placental ageing by measuring properties of mitochondria in healthy placentas collected at four different gestational ages ranging from 7 days before birth to 1 day before birth of the 19-day mouse pregnancy. We found that mitochondrial number increased per cell but that a marker of mitochondrial function was reduced. Proteins that control mitochondrial number, morphology and function also changed over time. This work lays the platform to understand how placental ageing contributes to adverse pregnancy outcomes related to altered pregnancy duration.
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Kim, H. R., K. Naruse, H. R. Lee, T. Wakayama, C. S. Park, and D. I. Jin. "51 PROTEOMICS ANALYSIS OF PLACENTOMEGALY IN CLONED MICE." Reproduction, Fertility and Development 19, no. 1 (2007): 143. http://dx.doi.org/10.1071/rdv19n1ab51.
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A variety of mammalian species have been cloned during the past few years. However, the success rate of somatic cell nuclear transfer in animals has been extremely low with many problems. Particularly, placentomegaly is a frequent finding in cloned mice and cattle (Wakayma et al. 1999 PNAS USA 96, 14 984–14 989; Niemann et al. 2000 Theriogenology 53, 21–34). To assess protein expression profile in the placentomagaly of cloned mice produced by nuclear transfer of embryonic stem cells, we have used global proteomics approach by 2-D gel electrophoresis and mass-spectrometry with the differential protein patterns using the 3 placentae of cloned mice and 4 normal mouse placentae. Proteins within isoelectric point range pH 4.0~9.0 and molecular weight range of 20–100 kDa separately were analyzed by 2-D gel electrophoresis with 3 replications of each sample. A total of approximately 3500 spots were detected 2-D gel. In the comparison of normal and cloned placenta samples, a total of 49 protein spots were expressed differentially, of which 28 spots were up-regulated proteins including alpha-fetoprotein, aspartyl aminopeptidase, placental lactogen 2, tissue inhibitor of metalloproteinase 2 (TIMP-2), etc., and 21 spots were down-regulated proteins including peroxiredoxin 6, creatine kinase, pre-B-cell colony-enhancing factor 1 (PBEF), etc. Eight spots could not be identified. One of differentially up-regulated proteins in cloned mouse placenta was identified as TIMP-2 protein that is related to extracellular matrix degradation and tissue remodeling processes. Western blot was performed with placental sample used in the 2-D gel electrophoresis analysis and normal mouse placenta samples on Days 11.5 to 18.5. Indeed, Western blot analysis confirmed a significant increase of TIMP-2 protein level in cloned mouse placenta compared with normal. The expression levels of TIMP-2 in normal mouse placenta were highest at the normal mid gestation (Day 13.5) and exhibited prominent decrease at late gestation period during normal pregnancy. However, the expression levels of TIMP-2 in placenta of cloned mice appeared to be similar to levels of mid gestation normal mouse placenta. And one of down-regulated protein in NT placenta was identified as PBEF protein that is known to be related to induction of spontaneous labor. PBEF protein level in cloned mice placenta was revealed to decrease remarkably compared with normal. The expression levels of PBEF in normal mice placenta exhibited a gradual decrease between Day 11.5 and Day 18.5 without complete depletion. However, the expression levels of PBEF in placenta of cloned mice appeared to be markedly lower than those of the same day normal placenta. In conclusion, abnormal expression of placental proteins associated with tissue remodeling and labor induction may be the cases of placentomegaly in cloned mice.
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Blumenstein, M., J. A. Keelan, J. M. Bowen-Shauver, and M. D. Mitchell. "Suppressors of cytokine signaling proteins in human preterm placental tissues." Journal of Molecular Endocrinology 35, no. 1 (August 2005): 165–75. http://dx.doi.org/10.1677/jme.1.01767.
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Decreased suppressors of cytokine signaling (SOCS) activity in human gestational tissues may play a part in the onset/progression of term labor. Since SOCS proteins negatively regulate cytokine-mediated inflammatory processes, we hypothesized that SOCS proteins are elevated in gestational tissues from spontaneous preterm deliveries with intrauterine infection. SOCS1, −2 and −3 mRNAs and proteins were detectable by RT-PCR and immunoblotting respectively, in preterm amnion, choriodecidua and placenta, irrespective of infection status. Immunoperoxidase staining localized SOCS1, −2 and −3 to all cell types of the gestational membranes, with infiltrating leukocytes reacting strongly in infected tissues. In villous placenta, SOCS was immunolocalized to the syncytiotrophoblast with marked staining of round mesenchymal cells, possibly Hofbauer cells. Nuclear SOCS staining was seen in amnion, chorion and placental syncytiotrophoblasts. SOCS proteins were, in general, significantly more abundant in placenta compared with amnion or choriodecidua. Placental SOCS1 and interleukin-1β concentrations were positively correlated (r2=0.47; P<0.05). However, no changes in SOCS levels in any tissues were observed with intrauterine infection. The relatively large amounts of SOCS proteins in the placenta may reflect a placenta-specific immunoprotective response to minimize the elaboration and effects of cytokines with potential to harm the placenta and fetus. Lack of labor-associated changes in SOCS levels suggests that the regulation of SOCS expression in preterm gestational tissues differs from those at term, perhaps reflecting roles in regulating placental somatotropic responses.
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Stanirowski, Paweł Jan, Dariusz Szukiewicz, Agata Majewska, Mateusz Wątroba, Michał Pyzlak, Dorota Bomba-Opoń, and Mirosław Wielgoś. "Differential Expression of Glucose Transporter Proteins GLUT-1, GLUT-3, GLUT-8 and GLUT-12 in the Placenta of Macrosomic, Small-for-Gestational-Age and Growth-Restricted Foetuses." Journal of Clinical Medicine 10, no. 24 (December 13, 2021): 5833. http://dx.doi.org/10.3390/jcm10245833.
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Placental transfer of glucose constitutes one of the major determinants of the intrauterine foetal growth. The objective of the present study was to evaluate the expression of glucose transporter proteins GLUT-1, GLUT-3, GLUT-8 and GLUT-12 in the placenta of macrosomic, small-for-gestational-age (SGA) and growth-restricted foetuses (FGR). A total of 70 placental tissue samples were collected from women who delivered macrosomic ≥4000 g (n = 26), SGA (n = 11), growth-restricted (n = 13) and healthy control neonates (n = 20). Computer-assisted quantitative morphometry of stained placental sections was performed to determine the expression of selected GLUT proteins. Immunohistochemical staining identified the presence of all glucose transporters in the placental tissue. Quantitative morphometric analysis performed for the vascular density-matched placental samples revealed a significant decrease in GLUT-1 and increase in GLUT-3 protein expression in pregnancies complicated by FGR as compared to other groups (p < 0.05). In addition, expression of GLUT-8 was significantly decreased among SGA foetuses (p < 0.05). No significant differences in GLUTs expression were observed in women delivering macrosomic neonates. In the SGA group foetal birth weight (FBW) was negatively correlated with GLUT-3 (rho = −0.59, p < 0.05) and positively with GLUT-12 (rho = 0.616, p < 0.05) placental expression. In addition, a positive correlation between FBW and GLUT-12 expression in the control group (rho = 0.536, p < 0.05) was noted. In placentas derived from FGR-complicated pregnancies the expression of two major glucose transporters GLUT-1 and GLUT-3 is altered. On the contrary, idiopathic foetal macrosomia is not associated with changes in the placental expression of GLUT-1, GLUT-3, GLUT-8 and GLUT-12 proteins.
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Schneider, H. "Placental transport function." Reproduction, Fertility and Development 3, no. 4 (1991): 345. http://dx.doi.org/10.1071/rd9910345.
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Placental transport provides a means of supplying nutrients to and removing metabolites from the fetus. Transport is based on substrate exchange and net flux from mother to fetus or vice versa and can be a result of a concentration difference or of unidirectional carrier-mediated transport. Blood flow regulates delivery to and removal from the area of placental exchange, and rapidly crossing compounds are dependent on blood flow for their rate of passage. There are substantial species differences in terms of flow rates normalized for fetal weight and also in terms of vascular arrangement. The barrier can be overcome via paracellular water-filled channels or via a transcellular route. Hydrophilic molecules that are not actively transported diffuse through paracellular channels, and the placentae of rodents and primates are much more permeable than the placenta of the sheep. Many different substrates such as glucose, amino acids, electrolytes and vitamins are transported by carrier systems. Transport proteins are located in the microvillous and basal membranes of the trophoblast. Asymmetry in the kinetics of binding results in differences in influx and efflux at the interface with maternal and fetal blood, allowing directional net flux across the placenta. Immunoglobulins are believed to cross by receptor-mediated endocytosis.
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Jeung, E. B., and H. Yang. "81 MEMBRANE AND CYTOSOLIC CALCIUM PROTEINS, TRPV6, PMCA1, NCKX3, NCX1 AND CaBP-28k, APPEAR TO BE DISTINCTLY REGULATED IN HUMAN CHORIOCARCINOMA AND PLACENTAL CELLS." Reproduction, Fertility and Development 24, no. 1 (2012): 153. http://dx.doi.org/10.1071/rdv24n1ab81.
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Preeclampsia is a pregnancy-specific disease characterised by de novo development of concurrent hypertension, proteinuria and oxidative stress in the placenta. In the placenta, intervillous blood flow increases after 10 weeks of gestation and results in exposure of trophoblast cells to oxygen. Hypoxia occurs during the development of placenta in the first trimester and is implicated in trophoblast differentiation. Ca2+ is a universal intracellular second messenger involved in many processes such as signal transduction, hormone secretion and programmed cell death. Human placental primary cell cultures were established from first-trimester human placentas (at 7 to 12 weeks of gestation). In this study, calcium-related proteins (CRPs; TRPV6, PMCA1, NCKX3 and CaBP-28k) were investigated at normoxia (5% CO2 in 95% air) or hypoxia (2% O2/93% N2/5%CO2) for 12 h in human placental cell line (BeWo) and human placental primary cell (hPC). We confirmed mRNA expression by real-time PCR and protein expression by Western blot analysis. The data were 2 or 3 individual experiments with triplicate samples and analysed by one-way ANOVA using Tukey's multiple comparison test. In hypoxia, the level of TRPV6 mRNA and protein was not changed, however, calcium transporters' (NCKX3, CaBP-28k) mRNA and protein expressions were significantly increased in hypoxic BeWo cell compared with control (normoxia). In addition, expression of PMCA1 mRNA and protein was decreased in hypoxic BeWo cells. In hPC, CRPs (TRPV6, PMCA1, NCKX3 and CaBP-28k) mRNA and protein expressions were significantly induced by hypoxic stress compared with control. These results, taken together, indicate that alterations of calcium transporters in hypoxic stress may be involved in calcium transport in the placenta and protection of the placental trophoblasts from the oxidative stress during the pregnancy.
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Ontsouka, Edgar, Alessandra Epstein, Sampada Kallol, Jonas Zaugg, Marc Baumann, Henning Schneider, and Christiane Albrecht. "Placental Expression of Bile Acid Transporters in Intrahepatic Cholestasis of Pregnancy." International Journal of Molecular Sciences 22, no. 19 (September 28, 2021): 10434. http://dx.doi.org/10.3390/ijms221910434.
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Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-related condition characterized by increased maternal circulating bile acids (BAs) having adverse fetal effects. We investigated whether the human placenta expresses specific regulation patterns to prevent fetal exposition to harmful amounts of BAs during ICP. Using real-time quantitative PCR, we screened placentae from healthy pregnancies (n = 12) and corresponding trophoblast cells (n = 3) for the expression of 21 solute carriers and ATP-binding cassette transporter proteins, all acknowledged as BA- and/or cholestasis-related genes. The placental gene expression pattern was compared between healthy women and ICP patients (n = 12 each). Placental SLCO3A1 (OATP3A1) gene expression was significantly altered in ICP compared with controls. The other 20 genes, including SLC10A2 (ASBT) and EPHX1 (EPOX, mEH) reported for the first time in trophoblasts, were comparably abundant in healthy and ICP placentae. ABCG5 was undetectable in all placentae. Placental SLC10A2 (ASBT), SLCO4A1 (OATP4A1), and ABCC2 mRNA levels were positively correlated with BA concentrations in ICP. Placental SLC10A2 (ASBT) mRNA was also correlated with maternal body mass index. We conclude that at the transcriptional level only a limited response of BA transport systems is found under ICP conditions. However, the extent of the transcriptional response may also depend on the severity of the ICP condition and the magnitude by which the maternal BA levels are increased.
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Robb, L., S. Rakar, and W. Alexander. "015.Disrupted decidualisation in SOCS3 gene mutant mice." Reproduction, Fertility and Development 16, no. 9 (2004): 15. http://dx.doi.org/10.1071/srb04abs015.
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Cytokines comprise a large family of secreted glycoproteins that regulate many fundamental biological processes. Cytokine signals are relayed to target cells via binding to cell surface receptors. The receptors signal via members of the Janus kinases (JAKs) and signal transduction and activators of transcription family (STATs). The SOCS proteins negatively regulate cytokine signalling by inhibiting components of the JAK/STAT pathway. Genetically modified mice in which individual SOCS genes are ablated have revealed key biological roles for these proteins. SOCS3 null mice die at mid gestation due to placental insufficiency. By embryonic Day (E) 9.5 there is a marked decrease in the spongiotrophoblast layer and an increase in trophoblast giant cells in SOCS3 null placentae. With increasing gestational age, there is progressive disorganisation of the SOCS3 null placental labyrinth. Takahashi et al. (1) used tetraploid aggregation to demonstrate that the placental defect was attributable to intrinsic defects in the SOCS3-deficient trophoblast cells or yolk sac endoderm. Based on evidence from in vitro assays, SOCS3 has a role in downstream negative regulation of signalling via a large number of cytokines. To identify the cytokine responsible for the placental phenotype, we crossed SOCS3 null embryos with mice lacking leukaemia inhibitory factor (LIF). This rescued the placental phenotype of the SOCS3 null mice, thereby demonstrating that alterations in LIF signalling are responsible for profound abnormalities of the murine placenta. (1) Takahashi et al. (2003) EMBO J. 22, 372–384.
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Antonson, Per, Gertrud U. Schuster, Ling Wang, Björn Rozell, Elin Holter, Per Flodby, Eckardt Treuter, Lars Holmgren, and Jan-Åke Gustafsson. "Inactivation of the Nuclear Receptor Coactivator RAP250 in Mice Results in Placental Vascular Dysfunction." Molecular and Cellular Biology 23, no. 4 (February 15, 2003): 1260–68. http://dx.doi.org/10.1128/mcb.23.4.1260-1268.2003.
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ABSTRACT Coactivators constitute a diverse group of proteins that are essential for optimal transcriptional activity of nuclear receptors. In the past few years many coactivators have been identified but it is still unclear whether these proteins interact indiscriminately with all nuclear receptors and whether there is some redundancy in their functions. We have previously cloned and characterized RAP250 (ASC-2/PRIP/TRBP/NRC), an LXXLL-containing coactivator for nuclear receptors. In order to study its biological role, Rap250 null mice were generated by gene targeting. Here we show that genetic disruption of Rap250 results in embryonic lethality at embryonic day (E) 13.5. Histological examination of placentas revealed a dramatically reduced spongiotrophoblast layer, a collapse of blood vessels in the region bordering the spongiotrophoblast, and labyrinthine layers in placentas from Rap250−/− embryos. These findings suggest that the lethality of Rap250−/− embryos is the result of obstructed placental blood circulation. Moreover, the transcriptional activity of PPARγ is reduced in fibroblasts derived from Rap250−/− embryos, suggesting that RAP250 is an essential coactivator for this nuclear receptor in the placenta. Our results demonstrate that RAP250 is necessary for placental development and thus essential for embryonic development.
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Seppälä, Markku, Koichi Iino, and Eeva-Marja Rutanen. "Placental Proteins in Oncology." Clinics in Obstetrics and Gynaecology 13, no. 3 (September 1986): 593–610. http://dx.doi.org/10.1016/s0306-3356(21)00034-0.
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Chassen, Stephanie Skuby, Veronique Ferchaud-Roucher, Madhulika B. Gupta, Thomas Jansson, and Theresa L. Powell. "Alterations in placental long chain polyunsaturated fatty acid metabolism in human intrauterine growth restriction." Clinical Science 132, no. 5 (March 15, 2018): 595–607. http://dx.doi.org/10.1042/cs20171340.
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Fatty acids (FA) are critical for fetal brain development and are transferred across the placenta by membrane-bound FA transport proteins (FATP), translocases (FAT/CD36), and cytosolic binding proteins (FABP). The cytosolic protein perilipin-2 aids in neutral lipid storage within lipid droplets. Decreased placental nutrient transport is believed to contribute to intrauterine growth restriction (IUGR); however, IUGR placental lipid transport and metabolism are poorly understood. We hypothesized that protein expression of FATPs, FABPs, and perilipin-2 in human placenta is decreased and placental lipid content and incorporation into lipid classes are reduced in IUGR. Placental tissue of idiopathic IUGR (n=25) and gestational age-matched, appropriately grown for gestational age (AGA) fetuses (n=19) was collected. We determined protein expression of FABP4 and perilipin-2 in placental homogenate and FATPs (2, 4, 6, CD36) in syncytiotrophoblast microvillous plasma membrane (MVM) by Western blot. Lipid droplet area (Oil Red O stain) and cellular FA content (GC/MS) were measured in chorionic villous tissue. MVM expression of FATP6 and CD36 was significantly increased in IUGR. The concentrations of seven n−6 and n−3 species long chain polyunsaturated FAs (LCPUFA) were significantly increased in the triglyceride fraction in IUGR vs AGA placenta. In summary, MVM FATP6 and CD36 protein expression is increased and LCPUFA are preferentially routed toward cellular storage in TG in the IUGR placenta, possibly to protect against oxidative stress associated with cellular FA accumulation. We speculate that these changes may be caused by impaired efflux of FA across the fetal-facing syncytiotrophoblast basal plasma membrane in IUGR placenta.
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Martinez, Cristina A., Ina Marteinsdottir, Ann Josefsson, Gunilla Sydsjö, Elvar Theodorsson, and Heriberto Rodriguez-Martinez. "Prenatal stress, anxiety and depression alter transcripts, proteins and pathways associated with immune responses at the maternal-fetal interface." Biology of Reproduction 106, no. 3 (December 22, 2021): 449–62. http://dx.doi.org/10.1093/biolre/ioab232.
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Abstract During pregnancy, the immune system is modified to allow developmental tolerance of the semi-allogeneic fetus and placenta to term. Pregnant women suffering from stress, anxiety, and depression show dysfunctions of their immune system that may be responsible for fetal and/or newborn disorders, provided that placental gene regulation is compromised. The present study explored the effects of maternal chronic self-perceived stress, anxiety, and depression during pregnancy on the expression of immune-related genes and pathways in term placenta. Pregnancies were clinically monitored with the Beck Anxiety Inventory (BAI) and Edinburgh Postnatal Depression Scale (EPDS). A cutoff threshold for BAI/EPDS of 10 divided patients into two groups: Index group (>10, n = 11) and a Control group (<10, n = 11), whose placentae were sampled at delivery. The placental samples were subjected to RNA-Sequencing, demonstrating that stress, anxiety, and depression during pregnancy induced a major downregulation of placental transcripts related to immune processes such as T-cell regulation, interleukin and cytokine signaling, or innate immune responses. Expression differences of main immune-related genes, such as CD46, CD15, CD8α & β ILR7α, and CCR4 among others, were found in the Index group (P < 0.05). Moreover, the key immune-like pathway involved in humoral and cellular immunity named “Primary immunodeficiency” was significantly downregulated in the Index group compared with Controls. Our results show that mechanisms ruling immune system functions are compromised at the maternal-fetal interface following self-perceived depressive symptoms and anxiety during pregnancy. These findings may help unveil mechanisms ruling the impact of maternal psychiatric symptoms and lead to new prevention/intervention strategies in complicated pregnancies.
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Dunwoodie, S. L., S. L. Withington, D. B. Sparrow, A. N. Scott, J. I. Preis, and J. Michalicek. "016.Role of cited genes in placental morphogenesis: studies in null mutant mice." Reproduction, Fertility and Development 16, no. 9 (2004): 16. http://dx.doi.org/10.1071/srb04abs016.
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Cited1 and Cited2 interact with CBP and p300. CBP/p300 bind numerous proteins and evidence exists, for Cited2 at least, that Cited binding prevents the binding of other proteins to CBP/p300. Since CBP/p300 interact with many proteins, can acetylate protein and DNA, and act as a ubiquitin ligase, it is likely that Cited1 and Cited2 function at a number of sites during development. We have generated mice that carry a null mutant allele for each of these genes. Analysis of null mutant embryos demonstrates that both Cited1 and Cited2 are required for normal embryonic development and survival. Although both Cited1 and Cited2 are expressed in the developing embryo and placenta, it appears that abnormal placental development and function is the cause of embryonic death. The defect that develops in the placentas of Cited1 null mutants is not apparent until late in gestation (16.5dpc). Cited1 null mutants are smaller than controls at birth and die during the early postnatal period. The placentas of these mutants are disorganised, with spongiotrophoblasts projecting in to the labyrinthine layer. In addition, resin casts of the maternal blood spaces within these placentas revealed extremely enlarged blood sinuses. We are searching for factors that could result in the increased size of the maternal blood sinuses. Cited2 null placentas and embryos are significantly smaller than controls; mutants die 3/4 the way through gestation (15.5dpc). The null mutant placentas have proportionally fewer spongiotrophoblasts, trophoblast giant cells and invasive trophoblasts. In addition, resin casts of fetal vasculature of the placenta reveal that the capillary network is underdeveloped. Through the isolation of trophoblast stem (TS) cells we are exploring the possibility that TS cell proliferation and/or differentiation is impaired due to a lack of Cited2. We suspect that the development of the phenotype may relate to the Hypoxia Inducible Factor-1a (HIF1a) transcription factor as Cited2 expression is induced by HIF1 and it acts to negatively regulate its activity.
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Wang, Joyce, Qing Qiu, Maliha Haider, Michael Bell, Andrée Gruslin, and Julian K. Christians. "Expression of pregnancy-associated plasma protein A2 during pregnancy in human and mouse." Journal of Endocrinology 202, no. 3 (May 26, 2009): 337–45. http://dx.doi.org/10.1677/joe-09-0136.
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Pregnancy-associated plasma protein-A and -A2 (PAPPA and PAPPA2) are proteases that cleave IGF binding proteins (IGFBPs) and thereby increase the bioavailability of growth factors. PAPPA has long been recognized as a marker of fetal genetic disorders and adverse pregnancy outcomes. In contrast, although PAPPA2 is also highly expressed in human placenta, its physiological importance is not clear. To establish whether mice will be a useful model for the study of PAPPA2, we compared the patterns of expression of PAPPA2 in the placentae of mouse and human. We show, for the first time, that Pappa2 is highly expressed in mouse placenta, as is the case in humans. Specifically, it is expressed at the interface of the maternal and fetal layers of the mouse placenta at all gestational stages studied (10.5–16.5 days post coitum). Similarly, PAPPA2 is expressed in the syncytiotrophoblast layer of human placental villi and is also detected in some invasive extravillous trophoblasts in the first trimester. These results are consistent with a model whereby PAPPA2 cleaves IGFBPs produced in the maternal decidua to promote feto-placental growth, and indicate that this protein may play analogous roles in human and mouse placenta. PAPPA2 protein is detectable in the circulation of pregnant mice and humans during the first trimester and at term, raising the possibility that PAPPA2 may be a useful biomarker of placental dysfunction. Pappa2 expression also shows specific localization within the mouse embryo and therefore may play roles in fetal development, independent of its action in the placenta.
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Guernsey, Michael W., Henri van Kruistum, David N. Reznick, Bart J. A. Pollux, and Julie C. Baker. "Molecular Signatures of Placentation and Secretion Uncovered in Poeciliopsis Maternal Follicles." Molecular Biology and Evolution 37, no. 9 (May 18, 2020): 2679–90. http://dx.doi.org/10.1093/molbev/msaa121.
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Abstract Placentation evolved many times independently in vertebrates. Although the core functions of all placentas are similar, we know less about how this similarity extends to the molecular level. Here, we study Poeciliopsis, a unique genus of live-bearing fish that have independently evolved complex placental structures at least three times. The maternal follicle is a key component of these structures. It envelops yolk-rich eggs and is morphologically simple in lecithotrophic species but has elaborate villous structures in matrotrophic species. Through sequencing, the follicle transcriptome of a matrotrophic, Poeciliopsis retropinna, and lecithotrophic, P. turrubarensis, species we found genes known to be critical for placenta function expressed in both species despite their difference in complexity. Additionally, when we compare the transcriptome of different river populations of P. retropinna, known to vary in maternal provisioning, we find differential expression of secretory genes expressed specifically in the top layer of villi cells in the maternal follicle. This provides some of the first evidence that the placental structures of Poeciliopsis function using a secretory mechanism rather than direct contact with maternal circulation. Finally, when we look at the expression of placenta proteins at the maternal–fetal interface of a larger sampling of Poeciliopsis species, we find expression of key maternal and fetal placenta proteins in their cognate tissue types of all species, but follicle expression of prolactin is restricted to only matrotrophic species. Taken together, we suggest that all Poeciliopsis follicles are poised for placenta function but require expression of key genes to form secretory villi.
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Lazo-de-la-Vega-Monroy, Maria-Luisa, Karen-Alejandra Mata-Tapia, Juan-Antonio Garcia-Santillan, Maria-Angelica Corona-Figueroa, Martha-Isabel Gonzalez-Dominguez, Hector-Manuel Gomez-Zapata, Juan-Manuel Malacara, Leonel Daza-Benitez, and Gloria Barbosa-Sabanero. "Association of placental nutrient sensing pathways with birth weight." Reproduction 160, no. 3 (September 2020): 455–68. http://dx.doi.org/10.1530/rep-20-0186.
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Birth weight (BW) is an important indicator for newborn health. Both high and low BW is associated with increased risks for adult metabolic diseases. AMPK (AMP-activated protein kinase), mTOR (mechanistic target of rapamycin), and insulin/IGF1 (insulin-like growth factor 1) pathways may function as placental sensors of maternal hormonal and nutritional status. However, the physiological role of these pathways in placenta has not been completely elucidated. To evaluate expression and activation of AMPK, mTOR, and insulin/IGF1 pathways and its association with placental weight (PW), BW, and maternal hormonal and metabolic status, we performed a cross-sectional study in placentas from non-obese mothers with SGA (n = 17), AGA (n = 19) and LGA (n = 10) newborns. We analyzed placental expression of total and phosphorylated key proteins from the AMPK, mTOR and insulin/IGF1 pathways. Maternal and cord blood hormones were determined by ELISA. AMPK and LKB1 activation correlated negatively with PW and BW, cord leptin, and pregestational BMI. Placental SIRT1 inversely correlated with BW, cord leptin, neonatal HOMA-IR, and maternal IGF1. PGC1α correlated negatively with PW and BW. Phosphorylated mTOR positively correlated with maternal glucose, PW and BW. IGF1R was lower in SGA. No changes in p-IGF1R, INSRb, total AKT or p-AKT were found, and pPDK1 was lower in SGA and LGA. These results suggest that placental AMPK, insulin/IGF1, and mTOR pathways may influence fetal growth, perhaps regulating placental physiology, even in metabolically healthy pregnancies. Our study highlights these nutrient sensing pathways as potential molecular mechanisms modulating placental adaptations and, thus, long-term metabolic health.
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Francis, Ellen C., Dana Dabelea, Kristen E. Boyle, Thomas Jansson, and Wei Perng. "Maternal Diet Quality Is Associated with Placental Proteins in the Placental Insulin/Growth Factor, Environmental Stress, Inflammation, and mTOR Signaling Pathways: The Healthy Start ECHO Cohort." Journal of Nutrition 152, no. 3 (November 26, 2021): 816–25. http://dx.doi.org/10.1093/jn/nxab403.
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ABSTRACT Background Maternal nutritional status affects placental function, which may underlie the intrauterine origins of obesity and diabetes. The extent to which diet quality is associated with placental signaling and which specific pathways are impacted is unknown. Objectives To examine sex-specific associations of maternal diet quality according to the Healthy Eating Index (HEI)—developed to align with recommendations from the Dietary Guidelines for Americans—with placental proteins involved in metabolism and mediators of environmental stress, inflammation, and growth factors. Methods Among 108 women from the Healthy Start cohort with a mean ± SD age of 29.0 ± 6.1 y and a prepregnancy BMI (in kg/m2) of 24.8 ± 5.3, we conducted multivariable linear regression analysis stratified by offspring sex. We adjusted for maternal race or ethnicity, age, education, prenatal smoking habits, and physical activity and tested for an association of maternal HEI >57 compared with ≤57 and the abundance and phosphorylation of key proteins involved in insulin/growth factor signaling; mediators of environmental stress, inflammation, and growth factors; mechanistic target of rapamycin signaling proteins; and energy sensing in placental villus samples. HEI >57 was chosen given its prior relevance among Healthy Start mother–child dyads. Results In adjusted models, HEI >57 was associated with greater abundance of insulin receptor β (0.80; 95% CI: 0.11, 1.49) in placentas of females. In males, maternal HEI >57 was associated with greater activation and abundance of select placental nutrient-sensing proteins and environmental stress, inflammation, and growth factor proteins (S6K1Thr389/S6K1: 0.81; 95% CI: 0.21, 1.41; JNK1Thr183/Tyr185/JNK1: 0.82; 95% CI: 0.27, 1.37; JNK2Thr183/Tyr185/JNK2: 0.57; 95% CI: 0.02, 1.11). Conclusions Higher-quality diet had sex-specific associations with placental protein abundance/phosphorylation. Given that these proteins have been correlated with neonatal anthropometry, our findings provide insight into modifiable factors and placental pathways that should be examined in future studies as potential links between maternal diet and offspring metabolic health. This trial was registered at clinicaltrials.gov as NCT02273297.
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Chard, T., and F. Olajide. "Endometrial protein PP14: a new test of endometrial function?" Reproductive Medicine Review 3, no. 1 (March 1994): 43–52. http://dx.doi.org/10.1017/s0962279900000764.
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The human endometrium produces a number of proteins which are at least partly specific to that tissue. Two of these proteins have been the subject of much recent work. They were originally called ‘placental protein 12’ and ‘placental protein 14’ (PP12 and PP14) because they were isolated by Hans Bohn from extracts of whole placentae. However, it is now clear that they arise from the maternal endometrium (decidua) rather than the fetal trophoblast. Placental protein 12 has been shown to be identical to the insulin-like growth factor binding protein-1 (IGFBP-1). It is produced in many normal tissues and its measurement probably does not provide a specific index of endometrial function. By contrast, PP14 is detectable only in ‘reproductive’ tissues and, in theory, might be an excellent clinical test of endometrial function.
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Quilang, Rachel, Emmanuelle Godinho, Kate Timms, Eleanor M. Scott, and Karen Forbes. "ODP434 Maternally-Derived Pancreatic Extracellular Vesicle Encompassed miRNAs Influence Placental Development in Pregnancies Complicated by Gestational Diabetes." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A671—A672. http://dx.doi.org/10.1210/jendso/bvac150.1389.
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Abstract Pregnancies affected by gestational diabetes (GDM) commonly result in large-for-gestational-age (LGA) infants; these infants have an increased risk of developing cardiometabolic complications compared to appropriate-for-gestational-age (AGA) infants. The mechanisms responsible are unclear but GDM/LGA is associated with altered placental development/function. We have recently reported altered levels of extracellular vesicle (EV) encapsulated miRNAs, including miR-375 (a pancreatic-specific miRNA) in maternal serum prior to the onset of LGA. We propose that the EVs containing miR-375 are produced by maternal pancreas, and that increased miR-375 in maternal circulation contributes to LGA by influencing placental development/function. Human placental tissue was collected from GDM pregnancies that delivered AGA (n=14) or LGA infants (n=10). Levels of mature miR-375 and primary transcript (pri-miR-375) were measured by QPCR. Mature miR-375 was increased in GDM-LGA (4.74-fold; p<0. 01) compared to GDM AGA placentae. Mature miR-375, but not pri-miR-375, was detected in human placenta suggesting that miR-375 is not produced in the placenta but instead is transported, potentially via EVs in maternal circulation. Intact human pancreatic islets (20,000 IEQ/patient) were obtained through the Integrated Islet Distribution Program (IIDP) from female donors of reproductive age. Islets were cultured in EV-depleted media containing 5.5mM (normoglycemia) or 7mM (mild hyperglycaemia) glucose for 3 days. Islet purity and viability were confirmed using dithizone incorporation and trypan blue exclusion, respectively. Media was collected at 24-hour intervals, pooled from all time points, concentrated and EVs were isolated by size exclusion chromatography. Confirmation of the presence of EVs was confirmed by electron microscopy (typical cup-shape morphology of EVs), nanoparticle tracking analysis (NTA; mean size of 83.5-163.2nm; concentration of 1.28×109-1.82×1010 particles/ml), Western blotting (EV-enriched proteins). QPCR confirmed that mature miR-375 was present in islet-derived EVs and revealed that levels were altered following culture in 7mM glucose compared to 5.5mM. Islet-derived EVs were labelled with maleimide-488 and uptake into explants of normal human term placenta was confirmed using fluorescent microscopy=3). miR-375 was overexpressed in normal human placental explants (by 30-fold, p<0. 05; n=6) using specific mimics (100nM for 72 hours) and TMT mass spectrometry was performed to assess the impact of miR-375 overexpression on the placental proteome. Functional enrichment analysis (FEA) was performed on differentially expressed proteins (DEP; P<0. 05; -0.41≥log2foldchange≥0.58) using over representation analysis and Ingenuity Pathway Analysis. This revealed that DEGs were significantly enriched in pathways associated with placental growth, mitochondrial function and glucose metabolism. Our data demonstrates that miR-375 is increased in the placenta in GDM/LGA and that this influences placental development/function. miR-375 does not appear to be produced in the placenta but instead, is likely released in EVs from maternal pancreas under conditions of hyperglycaemia and transported to the placenta, via maternal circulation. This provides insight into the potential mechanisms contributing to LGA in pregnancies complicated by GDM. Presentation: No date and time listed
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Delforce, Sarah J., Eugenie R. Lumbers, Stacey J. Ellery, Padma Murthi, and Kirsty G. Pringle. "Dysregulation of the placental renin–angiotensin system in human fetal growth restriction." Reproduction 158, no. 3 (September 2019): 237–45. http://dx.doi.org/10.1530/rep-18-0633.
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Fetal growth restriction (FGR) is a pregnancy complication wherein the foetus fails to reach its growth potential. The renin–angiotensin system (RAS) is a critical regulator of placental function, controlling trophoblast proliferation, angiogenesis and blood flow. The RAS significantly influences uteroplacental blood flow through the balance of its vasoconstrictive and vasodilatory pathways. Although the RAS is known to be dysregulated in placentae from women with preeclampsia, the expression of the RAS has not yet been studied in pregnancies compromised by FGR alone. This study investigated the mRNA expression and protein levels of RAS components in placentae from pregnancies compromised by FGR. Angiotensin II type 1 receptor (AGTR1) and angiotensin-converting enzyme 2 (ACE2) mRNA levels were reduced in FGR placentae compared with control (P = 0.012 and 0.018 respectively). Neprilysin (NEP) mRNA expression was lower in FGR placentae compared with control (P = 0.004). mRNA levels of angiotensinogen (AGT) tended to be higher in FGR placentae compared with control (P = 0.090). Expression of prorenin, AGT, angiotensin-converting enzyme (ACE) or ACE2 proteins were similar in control and FGR placentae. The renin-AGT reaction is a first order reaction so levels of expression of placental AGT determine levels of Ang II. Decreasing levels of ACE2 and/or NEP by limiting the production of Ang-(1-7), which is a vasodilator, and increasing placental Ang II levels (vasoconstrictor) may result in an imbalance between the vasoconstrictor and vasodilator arms of the placental RAS. Ultimately this dysregulation of the placental RAS could lead to reduced placental perfusion that is evident in FGR.
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Pogorelova, T. N., V. O. Gunko, N. A. Drukker, and V. A. Linde. "Proteins-markers of placental insufficiency." Biomeditsinskaya Khimiya 56, no. 5 (2010): 616–20. http://dx.doi.org/10.18097/pbmc20105605616.
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The proteomic analysis of the amniotic fluids of women with physiological pregnancy and pregnancy, complicated with placental insufficiency has been carried out on the II and III trimesters. The following difference in protein patterns have been recognized: i) appearance of several proteins lacking in physiological pregnancy; ii) absence of several proteins detectable during physiological pregnancy - hippocalcin-like protein 1, CDC37-like protein, NKG2D ligand 2 (II trimester), CDC37-like protein, NKG2D ligand 2 (III trimester). The established differences in the amniotic fluid spectrum, obviously, have the pathogenetic meaning in the placental insufficiency development. The revealed proteins of distinction may serve as markers of this obstetrical pathology.
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Klopper, A., A. Ahmed, N. Bersinger, and E. Macgregor. "Placental proteins in seminal fluid." Journal of Obstetrics and Gynaecology 6, no. 4 (January 1986): 290–93. http://dx.doi.org/10.3109/01443618609079225.
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Pogorelova, T. N., V. O. Gunko, N. A. Drukker, and V. A. Linde. "Proteins-markers of placental insufficiency." Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry 5, no. 2 (May 24, 2011): 135–38. http://dx.doi.org/10.1134/s1990750811020132.
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