Artykuły w czasopismach na temat „Defective trophoblast invasion”
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Ritter, Andreas, Susanne Roth, Nina-Naomi Kreis, Alexandra Friemel, Samira Catharina Hoock, Alice Steglich Souto, Christine Eichbaum i in. "Primary Cilia in Trophoblastic Cells". Hypertension 76, nr 5 (listopad 2020): 1491–505. http://dx.doi.org/10.1161/hypertensionaha.120.15433.
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The pathogenesis of preeclampsia, a pregnancy-related disease, is not completely understood. The primary cilium transduces a diverse array of signaling pathways important for vital cellular activities. Primary cilia were reported to facilitate trophoblastic cell invasion. We hypothesized their further functions in trophoblasts and were interested in related molecular mechanisms. We systematically examined the presence, length and percentage of the primary cilium, its mediated signal transduction, and its connection to trophoblast function. Various cellular and molecular methods were used including immunofluorescence staining, spheroid formation, gene analysis, invasion and tube formation assays with trophoblastic cell lines, primary trophoblasts, and placental tissues. We show that primary cilia are present in various trophoblastic cell lines derived from first trimester placentas. Cilia are also observable in primary trophoblasts, though in a small quantity. Importantly, primary cilia are shortened in trophoblastic cells derived from preeclamptic placentas. Mechanistically, interleukin-6, tumor necrosis factor-α or sera from patients with preeclampsia are able to reduce the length of primary cilia and impair the important sonic hedgehog signaling pathway. Functionally, trophoblastic cells with defective cilia display severe failures in their key functions, like migration, invasion and tube formation, also observed in trophoblastic cells depleted of the intraflagellar transport protein 88. This is accompanied by reduced gene expression of matrix metallopeptidases, vascular endothelial growth factor, and placental growth factor. This work highlights the significance of primary cilia in the functions of trophoblastic cells. Dysfunctional cilia may lead to compromised migration, invasion, and endothelial remodeling of trophoblastic cells, contributing to the development of preeclampsia.
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Bakardjiev, Anna I., Brian A. Stacy, Susan J. Fisher i Daniel A. Portnoy. "Listeriosis in the Pregnant Guinea Pig: a Model of Vertical Transmission". Infection and Immunity 72, nr 1 (styczeń 2004): 489–97. http://dx.doi.org/10.1128/iai.72.1.489-497.2004.
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ABSTRACT Feto-placental infections represent a major cause of pregnancy complications, and yet the underlying molecular and cellular mechanisms of vertical transmission are poorly understood. Listeria monocytogenes, a facultative intracellular pathogen, is one of a group of pathogens that are known to cause feto-placental infections in humans and other mammals. The purpose of this study was to evaluate possible mechanisms of vertical transmission of L. monocytogenes. Humans and guinea pigs have a hemochorial placenta, where a single layer of fetally derived trophoblasts separates maternal from fetal circulation. We characterized L. monocytogenes infection of the feto-placental unit in a pregnant guinea pig model and in primary human trophoblasts and trophoblast-derived cell lines. The clinical manifestations of listeriosis in the pregnant guinea pigs and the tropism of L. monocytogenes to the guinea pig placenta resembled those in humans. Trophoblast cell culture systems were permissive for listerial growth and cell-to-cell spread and revealed that L. monocytogenes deficient in internalin A, a virulence factor that mediates invasion of nonphagocytic cells, was 100-fold defective in invasion. However, crossing of the feto-placental barrier in the guinea pig model was independent of internalin A, suggesting a negligible role for internalin-mediated direct invasion of trophoblasts in vivo. Further understanding of vertical transmission of L. monocytogenes will help in designing more effective means of treatment and disease prevention.
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Abbas, Yassen, Carolin Melati Oefner, William J. Polacheck, Lucy Gardner, Lydia Farrell, Andrew Sharkey, Roger Kamm, Ashley Moffett i Michelle L. Oyen. "A microfluidics assay to study invasion of human placental trophoblast cells". Journal of The Royal Society Interface 14, nr 130 (maj 2017): 20170131. http://dx.doi.org/10.1098/rsif.2017.0131.
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Pre-eclampsia, fetal growth restriction and stillbirth are major pregnancy disorders throughout the world. The underlying pathogenesis of these diseases is defective placentation characterized by inadequate invasion of extravillous placental trophoblast cells into the uterine arteries. How trophoblast invasion is controlled remains an unanswered question but is influenced by maternal uterine immune cells called decidual natural killer cells. Here, we describe an in vitro microfluidic invasion assay to study the migration of primary human trophoblast cells. Each experiment can be performed with a small number of cells making it possible to conduct research on human samples despite the challenges of isolating primary trophoblast cells. Cells are exposed to a chemical gradient and tracked in a three-dimensional microenvironment using real-time high-resolution imaging, so that dynamic readouts on cell migration such as directionality, motility and velocity are obtained. The microfluidic system was validated using isolated trophoblast and a gradient of granulocyte-macrophage colony-stimulating factor, a cytokine produced by activated decidual natural killer cells. This microfluidic model provides detailed analysis of the dynamics of trophoblast migration compared to previous assays and can be modified in future to study in vitro how human trophoblast behaves during placentation.
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Liao, Jiujiang, Yangxi Zheng, Mingyu Hu, Ping Xu, Li Lin, Xiyao Liu, Yue Wu i in. "Impaired Sphingosine-1-Phosphate Synthesis Induces Preeclampsia by Deactivating Trophoblastic YAP (Yes-Associated Protein) Through S1PR2 (Sphingosine-1-Phosphate Receptor-2)-Induced Actin Polymerizations". Hypertension 79, nr 2 (luty 2022): 399–412. http://dx.doi.org/10.1161/hypertensionaha.121.18363.
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Incomplete spiral artery remodeling, caused by impaired extravillous trophoblast invasion, is a fundamental pathogenic process associated with malplacentation and the development of preeclampsia. Nevertheless, the mechanisms controlling this regulation of trophoblast invasion are largely unknown. We report that sphingosine-1-phosphate synthesis and expression is abundant in healthy trophoblast, whereas in pregnancies complicated by preeclampsia the placentae are associated with reduced sphingosine-1-phosphate and lower SPHK1 (sphingosine kinase 1) expression and activity. In vivo inhibition of sphingosine kinase 1 activity during placentation in pregnant mice led to decreased placental sphingosine-1-phosphate production and defective placentation, resulting in a preeclampsia phenotype. Moreover, sphingosine-1-phosphate increased HTR8/SVneo (immortalized human trophoblst cells) cell invasion in a Hippo-signaling–dependent transcriptional coactivator YAP (Yes-associated protein) dependent manner, which is activated by S1PR2 (sphingosine-1-phosphate receptor-2) and downstream RhoA (Ras homolog gene family, member A)/ROCK (Rho-associated protein kinase) induced actin polymerization. Mutation-based YAP-5SA (S61A, S109A, S127A, S164A, S381A) demonstrated that sphingosine-1-phosphate activation of YAP could be either dependent or independent of Hippo signaling. Together, these findings suggest a novel pathogenic pathway of preeclampsia via disrupted sphingosine-1-phosphate metabolism and signaling-induced, interrupted actin dynamics and YAP deactivation; this may lead to potential novel intervention targets for the prevention and management of preeclampsia.
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Che, Guanglu, Yanyun Wang, Bin Zhou, Linbo Gao, Tao Wang, Fang Yuan i Lin Zhang. "Knockdown of Heparanase Suppresses Invasion of Human Trophoblasts by Activating p38 MAPK Signaling Pathway". Disease Markers 2018 (2018): 1–10. http://dx.doi.org/10.1155/2018/7413027.
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Preeclampsia is a pregnancy-related disease with increasing maternal and perinatal morbidity and mortality worldwide. Defective trophoblast invasion is considered to be a major factor in the pathophysiological mechanism of preeclampsia. Heparanase, the only endo-β-glucuronidase in mammalian cells, has been shown to be abnormally expressed in the placenta of preeclampsia patients in our previous study. The biological role and potential mechanism of heparanase in trophoblasts remain unclear. In the present study, stably transfected HTR8/SVneo cell lines with heparanase overexpression or knockdown were constructed. The effect of heparanase on cellular proliferation, apoptosis, invasion, tube formation, and potential pathways in trophoblasts was explored. Our results showed that overexpression of heparanase promoted proliferation and invasion. Knockdown of heparanase suppressed proliferation, invasion, and tube formation but induced apoptosis. These findings reveal that downregulation of heparanase may contribute to defective placentation and plays a crucial role in the pathogenesis of preeclampsia. Furthermore, increased activation of p38 MAPK in heparanase-knockdown HTR8/SVneo cell was shown by MAPK pathway phosphorylation array and Western blotting assay. After pretreatment with 3 specific p38 MAPK inhibitors (BMS582949, SB203580, or BIRB796), inadequate invasion in heparanase-knockdown HTR8/SVneo cell was rescued. That indicates that knockdown of heparanase decreases HTR8/SVneo cell invasion through excessive activation of the p38 MAPK signaling pathway. Our study suggests that heparanase can be a potential predictive biomarker for preeclampsia at an early stage of pregnancy and represents a promising therapeutic target for the treatment of preeclampsia.
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Singh, A., J. Keelan i F. Sieg. "275. Neuronal regeneration peptide (NRP): a novel trophoblast migration and survival enhancing factor". Reproduction, Fertility and Development 17, nr 9 (2005): 113. http://dx.doi.org/10.1071/srb05abs275.
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Autocrine and paracrine factors regulate survival, proliferation, migration and invasion of placental cytotrophoblasts cells. While trophoblast migration appears to be tightly controlled, the nature of the chemoattractive factors that facilitate and direct trophoblast invasion remains undefined. Our group recently discovered a chemottractive factor (NRP) that exerts its biological activities on the CNS. Studies of NRP actions reveal extensive influences on postnatal neuronal migration, differentiation and survival. Based on the neuronal activities of NRPs and parallels between neuronal and placental cell behavior patterns, we speculated that NRPs could be involved in placental development. Migration assays were performed over 22 h using Boyden chambers pre-coated with NRP and laminin (n = 6 chambers per condition), to test the effect of NRPs on trophoblast migration. CTBs were isolated from term placentas by trypsin digestion and Percoll purification, and experiments were conducted within 6 h. Trophoblasts were seeded into the inner chamber (50000 cells/well) in M199 media supplemented with 10% FBS and antibiotics. Total number of cells migrating was counted. Migration was increased by 95 ± 14 % (mean ± SEM) in the presence of 100 fM NRP (P = 0.0016, t-test) compared to controls (bovine serum albumin). Survival assays were also performed using both primary trophoblasts and Jar choriocarcinoma cells. Apoptosis over 48 h, induced by treatment with TNF-α (5 ng/mL) and IFN-γ (100 U/mL), was completely abrogated by 10 pM NRP in Jar cells and 1pM in primary trophoblasts, as judged by MTT assay (mitochondrial activity). Inadequate placentation is implicated in the pathogenesis of a number of serious pregnancy disorders such as preeclampsia. Our findings suggest important roles for NRPs in regulating trophoblast migration and survival. The possibility that defective NRP actions may be involved in various placental pathologies, or that NRPs could be used pharmacologically to augment placentation, remain to be explored.
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Tsai, Kary Y. F., Benton Tullis, Katrina L. Breithaupt, Rylan Fowers, Nelson Jones, Samuel Grajeda, Paul R. Reynolds i Juan A. Arroyo. "A Role for RAGE in DNA Double Strand Breaks (DSBs) Detected in Pathological Placentas and Trophoblast Cells". Cells 10, nr 4 (9.04.2021): 857. http://dx.doi.org/10.3390/cells10040857.
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Impaired DNA damage responses are associated with several diseases, including pregnancy complications. Recent research identified an ATM-kinase dependent function for the nuclear isoform of the receptor for advanced glycation end-products (RAGE) during double strand break (DSB)-repair. RAGE contributes to end-resectioning of broken DNA sites by binding with the MRE11-Rad50-Nbs1 (MRN) complex. Placental research is limited regarding the impact of genomic instability and the mechanism for potential repair. We tested the hypothesis regarding the involvement of RAGE during the repair of placental DNA-DSBs. We first identified that the pregnancy complications of PE and preterm labor (PTL) experience loss of genomic integrity and an in vitro trophoblast cell model was used to characterize trophoblast DSBs. Colocalized immunofluorescence of γ-H2AX and RAGE support the potential involvement of RAGE in cellular responses to DNA-DSBs. Immunoblotting for both molecules in PE and PTL placenta samples and in trophoblast cells validated a connection. Co-immunoprecipitation studies revealed interactions between RAGE and pATM and MRE11 during DNA-DSBs. Reduced cellular invasion confirmed the role of genomic instability in trophoblastic function. Collectively, these experiments identified genomic instability in pregnancy complications, the impact of defective DNA on trophoblast function, and a possible RAGE-mediated mechanism during DNA-DSB repair.
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Meister, Sarah, Laura Hahn, Susanne Beyer, Corinna Paul, Sophie Mitter, Christina Kuhn, Viktoria von Schönfeldt i in. "Regulation of Epigenetic Modifications in the Placenta during Preeclampsia: PPARγ Influences H3K4me3 and H3K9ac in Extravillous Trophoblast Cells". International Journal of Molecular Sciences 22, nr 22 (18.11.2021): 12469. http://dx.doi.org/10.3390/ijms222212469.
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The aim of this study was to analyze the expression of peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor α (RxRα), a binding heterodimer playing a pivotal role in the successful trophoblast invasion, in the placental tissue of preeclamptic patients. Furthermore, we aimed to characterize a possible interaction between PPARγ and H3K4me3 (trimethylated lysine 4 of the histone H3), respectively H3K9ac (acetylated lysine 9 of the histone H3), to illuminate the role of histone modifications in a defective trophoblast invasion in preeclampsia (PE). Therefore, the expression of PPARγ and RxRα was analyzed in 26 PE and 25 control placentas by immunohistochemical peroxidase staining, as well as the co-expression with H3K4me3 and H3K9ac by double immunofluorescence staining. Further, the effect of a specific PPARγ-agonist (Ciglitazone) and PPARγ-antagonist (T0070907) on the histone modifications H3K9ac and H3K4me3 was analyzed in vitro. In PE placentas, we found a reduced expression of PPARγ and RxRα and a reduced co-expression with H3K4me3 and H3K9ac in the extravillous trophoblast (EVT). Furthermore, with the PPARγ-antagonist treated human villous trophoblast (HVT) cells and primary isolated EVT cells showed higher levels of the histone modification proteins whereas treatment with the PPARγ-agonist reduced respective histone modifications. Our results show that the stimulation of PPARγ-activity leads to a reduction of H3K4me3 and H3K9ac in trophoblast cells, but paradoxically decreases the nuclear PPARγ expression. As the importance of PPARγ, being involved in a successful trophoblast invasion has already been investigated, our results reveal a pathophysiologic connection between PPARγ and the epigenetic modulation via H3K4me3 and H3K9ac in PE.
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Sebire, N. J. "Defective endovascular trophoblast invasion in primary antiphospholipid antibody syndrome-associated early pregnancy failure". Human Reproduction 17, nr 4 (1.04.2002): 1067–71. http://dx.doi.org/10.1093/humrep/17.4.1067.
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Ridder, Anna, Veronica Giorgione, Asma Khalil i Basky Thilaganathan. "Preeclampsia: The Relationship between Uterine Artery Blood Flow and Trophoblast Function". International Journal of Molecular Sciences 20, nr 13 (2.07.2019): 3263. http://dx.doi.org/10.3390/ijms20133263.
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Maternal uterine artery blood flow is critical to maintaining the intrauterine environment, permitting normal placental function, and supporting fetal growth. It has long been believed that inadequate transformation of the maternal uterine vasculature is a consequence of primary defective trophoblast invasion and leads to the development of preeclampsia. That early pregnancy maternal uterine artery perfusion is strongly associated with placental cellular function and behaviour has always been interpreted in this context. Consistently observed changes in pre-conceptual maternal and uterine artery blood flow, abdominal pregnancy implantation, and late pregnancy have been challenging this concept, and suggest that abnormal placental perfusion may result in trophoblast impairment, rather than the other way round. This review focuses on evidence that maternal cardiovascular function plays a significant role in the pathophysiology of preeclampsia.
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B R, Balaji, i K. N. Pujari. "Cross Sectional Study of Zinc, Copper and Magnesium Levels in Preeclampsia and Normal Pregnancy". International Journal of Research and Review 8, nr 10 (8.10.2021): 33–36. http://dx.doi.org/10.52403/ijrr.20211006.
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Preeclampsia is a pregnancy related high blood pressure disorder. It involves defective trophoblast invasion and decreased spiral artery remodelling. Alterations in micronutrients have been identified as one of the risk factor of preeclampsia. In this study we have estimated the levels of zinc, copper, iron and magnesium in preeclampsia and normal pregnant women. Our study revealed a significant decrease of zinc, copper and magnesium levels and significant increase of iron levels in preeclampsia compared to normal pregnant women. Thus assessment of micronutrients in pregnancy helps in decreasing the incidence of preeclampsia. Keywords: Preeclampsia, Zinc, Copper, Iron, Magnesium.
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Papageorghiou, A. T., F. Prefumo, K. Leslie, D. C. Gaze, P. O. Collinson i B. Thilaganathan. "Defective endovascular trophoblast invasion in the first trimester is associated with increased maternal serum ischemia-modified albumin". Human Reproduction 23, nr 4 (31.01.2008): 803–6. http://dx.doi.org/10.1093/humrep/den029.
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Barrientos, G., M. Pussetto, M. Rose, A. C. Staff, S. M. Blois i J. E. Toblli. "Defective trophoblast invasion underlies fetal growth restriction and preeclampsia-like symptoms in the stroke-prone spontaneously hypertensive rat". MHR: Basic science of reproductive medicine 23, nr 7 (27.04.2017): 509–19. http://dx.doi.org/10.1093/molehr/gax024.
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Gerasimova, Elizaveta M., Sergey A. Fedotov, Daniel V. Kachkin, Elena S. Vashukova, Andrey S. Glotov, Yury O. Chernoff i Aleksandr A. Rubel. "Protein Misfolding during Pregnancy: New Approaches to Preeclampsia Diagnostics". International Journal of Molecular Sciences 20, nr 24 (7.12.2019): 6183. http://dx.doi.org/10.3390/ijms20246183.
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Preeclampsia (PE) is a multisystem heterogeneous complication of pregnancy remaining a leading cause of maternal and perinatal morbidity and mortality over the world. PE has a large spectrum of clinical features and symptoms, which make diagnosis challenging. Despite a long period of studying, PE etiology is still unclear and there are no reliable rapid tests for early diagnosis of this disease. During the last decade, it was shown that proteins misfolding and aggregation are associated with PE. Several proteins, including amyloid beta peptide, transthyretin, alpha-1 antitrypsin, albumin, IgG k-free light chains, and ceruloplasmin are dysregulated in PE, resulting in toxic deposition of amyloid-like aggregates in the placenta and body fluids. It is also possible that aggregated proteins induce defective trophoblast invasion, placental ischemia, ER stress, and promote PE manifestation. The fact that protein aggregation is an emerging biomarker of PE provides an opportunity to develop new diagnostic approaches based on amyloids special features, such as Congo red (CR) staining and thioflavin T (ThT) enhanced fluorescence.
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Carvajal, Jorge A. "Docosahexaenoic Acid Supplementation Early in Pregnancy May Prevent Deep Placentation Disorders". BioMed Research International 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/526895.
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Uteroplacental ischemia may cause preterm birth, either due to preterm labor, preterm premature rupture of membranes, or medical indication (in the presence of preeclampsia or fetal growth restriction). Uteroplacental ischemia is the product of defective deep placentation, a failure of invasion, and transformation of the spiral arteries by the trophoblast. The failure of normal placentation generates a series of clinical abnormalities nowadays called “deep placentation disorders”; they include preeclampsia, fetal growth restriction, preterm labor, preterm premature rupture of membranes, in utero fetal death, and placental abruption. Early reports suggested that a LC-PUFAs (long chain polyunsaturated fatty acids) rich diet reduces the incidence of deep placentation disorders. Recent randomized controlled trials are inconsistent to show the benefit of docosahexaenoic acid (DHA) supplementation during pregnancy to prevent deep placentation disorders, but most of them showed that DHA supplementation was associated with lower risk of early preterm birth. We postulate that DHA supplementation, early in pregnancy, may reduce the incidence of deep placentation disorders. If our hypothesis is correct, DHA supplementation, early in pregnancy, will become a safe and effective strategy for primary prevention of highly relevant pregnancy diseases, such as preterm birth, preeclampsia, and fetal growth restriction.
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Williams, Paula J., Judith N. Bulmer, Roger F. Searle, Barbara A. Innes i Stephen C. Robson. "Altered decidual leucocyte populations in the placental bed in pre-eclampsia and foetal growth restriction: a comparison with late normal pregnancy". REPRODUCTION 138, nr 1 (lipiec 2009): 177–84. http://dx.doi.org/10.1530/rep-09-0007.
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Alterations in the balance of leucocyte populations in uterine decidua may lead to the generation of an unfavourable cytokine environment that is associated with unsuccessful pregnancy. Single and double immunohistochemical labelling was used to examine leucocyte populations in decidua from normal third trimester, foetal growth-restricted and pre-eclamptic pregnancies. Placental bed biopsies from 12 women undergoing elective Caesarean section with no hypertension or foetal growth restriction (FGR), 8 women with FGR without maternal hypertension and 12 women with pre-eclampsia (PE) were used to quantify decidual CD56+ uterine NK cells, CD14+ macrophages, CD3+T-lymphocytes and CD8+ lymphocytes. CD3+CD56+, CD8+CD56+ and CD161+CD3+ double-labelled cells in decidua were compared in PE and control decidua. Decidual CD3+T-lymphocytes (P<0.01), CD8+ cytotoxic T-lymphocytes (P<0.05), CD14+ macrophages (P<0.0001) and CD56+ uterine natural killer (uNK) cells (P=0.01) were decreased in placental bed biopsies from women with PE compared with control third trimester decidua. By contrast, only CD56+ uNK cells were decreased in FGR decidua (P<0.05). Double-positive CD8+CD56+ cells were also decreased in PE compared with control third trimester decidua (P<0.05). The reduction in specific leucocyte subset numbers in PE and uNK cells in FGR suggests that altered local cytokine balance may be important in defective trophoblast invasion and spiral artery transformation in these pathological pregnancies.
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McCracken, Sharon A., Sean K. M. Seeho, Tamara Carrodus, Jenny H. Park, Narelle Woodland, Eileen D. M. Gallery, Jonathan M. Morris i Anthony W. Ashton. "Dysregulation of Oxygen Sensing/Response Pathways in Pregnancies Complicated by Idiopathic Intrauterine Growth Restriction and Early-Onset Preeclampsia". International Journal of Molecular Sciences 23, nr 5 (2.03.2022): 2772. http://dx.doi.org/10.3390/ijms23052772.
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Preeclampsia (PE) and intrauterine growth restriction (IUGR) are the leading causes of maternal and fetal morbidity/mortality. The central deficit in both conditions is impaired placentation due to poor trophoblast invasion, resulting in a hypoxic milieu in which oxidative stress contributes to the pathology. We examine the factors driving the hypoxic response in severely preterm PE (n = 19) and IUGR (n = 16) placentae compared to the spontaneous preterm (SPT) controls (n = 13) using immunoblotting, RT-PCR, immunohistochemistry, proximity ligation assays, and Co-IP. Both hypoxia-inducible factor (HIF)-1α and HIF-2α are increased at the protein level and functional in pathological placentae, as target genes prolyl hydroxylase domain (PHD)2, PHD3, and soluble fms-like tyrosine kinase-1 (sFlt-1) are increased. Accumulation of HIF-α-subunits occurs in the presence of accessory molecules required for their degradation (PHD1, PHD2, and PHD3 and the E3 ligase von Hippel–Lindau (VHL)), which were equally expressed or elevated in the placental lysates of PE and IUGR. However, complex formation between VHL and HIF-α-subunits is defective. This is associated with enhanced VHL/DJ1 complex formation in both PE and IUGR. In conclusion, we establish a significant mechanism driving the maladaptive responses to hypoxia in the placentae from severe PE and IUGR, which is central to the pathogenesis of both diseases.
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Szewczyk, Grzegorz, Michał Pyzlak, Jakub Klimkiewicz, Wacław Śmiertka, Magdalena Miedzińska-Maciejewska i Dariusz Szukiewicz. "Mast Cells and Histamine: Do They Influence Placental Vascular Network and Development in Preeclampsia?" Mediators of Inflammation 2012 (2012): 1–5. http://dx.doi.org/10.1155/2012/307189.
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The physiological course of pregnancy is closely related to adequate development of the placenta. Shallow invasion of trophoblast as well as decreased development of the placental vascular network are both common features of preeclampsia. To better understand the proangiogenic features of mast cells, in this study we aim to identify the potential relationship between the distribution of mast cells within the placenta and vascular network development.Material and Methods. Placentas from preeclampsia-complicated pregnancies () and from physiological pregnancies () were acquired after cesarean section. The concentration of histamine was measured, and immunohistochemical staining for mast cell tryptase was performed. Morphometric analysis was then performed.Results. We noticed significant differences between the examined groups. Notably, in the preeclampsia group compared to the control group, we observed a higher mean histamine concentration, higher mast cell density (MCD), lower mean mast cell (MMCA) and lower vascular/extravascular (V/EVT) index. In physiological pregnancies, a positive correlation was observed between the histamine concentration and V/VEVT index as well as MCD and the V/VEVT index. In contrast, a negative correlation was observed between MMCA and the V/EVT index in physiological pregnancies.Conclusions. Based on the data from our study, we suggest that a differential distribution of mast cells and corresponding changes in the concentration of histamine are involved in the defective placental vascularization seen in preeclamptic placentas.
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Nadkarni, Suchita, Joanne Smith, Amanda N. Sferruzzi-Perri, Agata Ledwozyw, Madhav Kishore, Robert Haas, Claudio Mauro i in. "Neutrophils induce proangiogenic T cells with a regulatory phenotype in pregnancy". Proceedings of the National Academy of Sciences 113, nr 52 (12.12.2016): E8415—E8424. http://dx.doi.org/10.1073/pnas.1611944114.
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Although neutrophils are known to be fundamental in controlling innate immune responses, their role in regulating adaptive immunity is just starting to be appreciated. We report that human neutrophils exposed to pregnancy hormones progesterone and estriol promote the establishment of maternal tolerance through the induction of a population of CD4+ T cells displaying a GARP+CD127loFOXP3+ phenotype following antigen activation. Neutrophil-induced T (niT) cells produce IL-10, IL-17, and VEGF and promote vessel growth in vitro. Neutrophil depletion during murine pregnancy leads to abnormal development of the fetal-maternal unit and reduced empbryo development, with placental architecture displaying poor trophoblast invasion and spiral artery development in the maternal decidua, accompanied by significantly attenuated niT cell numbers in draining lymph nodes. Using CD45 congenic cells, we show that induction of niT cells and their regulatory function occurs via transfer of apoptotic neutrophil-derived proteins, including forkhead box protein 1 (FOXO1), to T cells. Unlike in women with healthy pregnancies, neutrophils from blood and placental samples of preeclamptic women fail to induce niT cells as a direct consequence of their inability to transfer FOXO1 to T cells. Finally, neutrophil-selective FOXO1 knockdown leads to defective placentation and compromised embryo development, similar to that resulting from neutrophil depletion. These data define a nonredundant function of neutrophil–T cell interactions in the regulation of vascularization at the maternal–fetal interface.
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Potapov, V. O. "Biological role of nitric oxide donors in pregravid preparation of women with luteal phase deficiency". Infusion & Chemotherapy, nr 3.2 (15.12.2020): 247–49. http://dx.doi.org/10.32902/2663-0338-2020-3.2-247-249.
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Background. At the menstrual cycle beginning there is a proliferation of endometrial cells under the influence of oestrogen, and in the second half, after ovulation there is a differentiation and hypertrophy of cells under the influence of corpus luteum progesterone. Lutein phase deficiency (LPD) can be divided into 3 types: lack of progesterone production (corpus luteum is absent), low progesterone level (corpus luteum hypofunction), and reduction of progesterone production period (short period of corpus luteum existence, luteal phase duration <11 days).
Objective. To describe the role of nitric oxide (NO) donors in women with LPD.
Materials and methods. Analysis of literature data on this issue.
Results and discussion. The main adverse outcome of LPD is the absence or defective transformation and reception of the endometrium required for successful fertilization of the egg. In case of progesterone deficiency, the depth of trophoblast invasion decreases, resulting in abnormal placental development and inadequate uteroplacental blood flow. The latter can further lead to antenatal foetal death and miscarriage, preeclampsia and eclampsia, placental dysfunction. LPD should be suspected in patients with infertility, abnormal uterine bleeding, severe premenstrual syndrome, endometrial hyperplasia, and habitual miscarriage. Ultrasound signs of LPD include the absence of a dominant follicle, absence of ovulation in the presence of a mature follicle (persistence), absence of corpus luteum in the 2nd phase of the cycle, endometrial thickness in the secretion phase <9 mm, increased echogenicity only in the peripheral parts of the endometrium or three-layered endometrium. Functional tests for the detection of LPD include the basal temperature measurement and examination of smears (hypolutein type of smear, preservation of the symptom of cervical mucus crystallization in the 2nd phase of the cycle). A key element of pregravid preparation for women with LPD is the progesterone donation (in oil solution, in etiloleate or micronized). The therapeutic efficacy of different commercial progesterone drugs is the same. Progesterone helps to prepare the endometrium for trophoblast invasion and promotes uterine hypotension. Incomplete secretory transformation of the endometrium during the treatment with progesterone drugs occurs in case of inadequate blood supply to the endometrium due to low density of functional vessels or insufficient content of NO in the endometrium. Back in the late 90’s of last century, it was shown that NO acts as a powerful uterine relaxant, and reduction of its concentration leads to miscarriage. In humans, NO is produced from L-arginine, however, obtaining the required dose of the latter with food is not always possible. When L-arginine (Tivortin aspartate, “Yuria-Pharm”) is used as a NO donor, peripheral vascular dilatation and neoangiogenesis occur, which improves blood supply and endometrial trophic processes; stimulation of gene transcription and cell cycle, which increases the cell population and physiological thickness of the endometrium; regulation of sex hormone synthesis and expression of their receptors, which increases the receptivity of the endometrium. The regimen of Tivortin aspartate administration is the following: 5 ml (1 g) 6 times per day during the menstrual cycle. According to the results of our own study, L-arginine increases the biological effect of progesterone on the endometrium, promotes a more successful restoration of its physiological structure and thickness in women with LPD. The inclusion of L-arginine in the pregravid preparation of women with LPD showed a 1.9-fold decrease in the infertility incidence, a 3.3-fold increase in the number of pregnancies and births, and a 3.4-fold decrease in the number of miscarriages.
Conclusions. 1. The main adverse outcome of LPD is the absence or defective transformation and reception of the endometrium required for successful fertilization of the egg. 2. Usage of L-arginine (Tivortin aspartate) as a donor of NO promotes dilatation of peripheral vessels and neoangiogenesis, stimulation of the cell cycle, regulation of the synthesis of sex hormones. 3. Inclusion of L-arginine in the pregravid preparation of women with LPD leads to the decrease in infertility, to the increase in the number of pregnancies and births and to the decrease in the number of miscarriages.
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Ventskovsky, B. M., i V. G. Zhegulovych. "ON THE PATHOGENESIS OF PRE-ECLAMPSIA". Medical Science of Ukraine (MSU) 15, nr 1-2 (6.12.2019): 101–6. http://dx.doi.org/10.32345/2664-4738.1-2.2019.15.
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Relevance. To date, there is no pathogenetic treatment for pre-eclampsia because the etiology and pathogenesis of this pathology are still poorly understood. Therefore, the analysis of possible causes and mechanisms of pre-eclampsia is an urgent problem, as it will help to choose the right tactics for pregnant women with pre-eclampsia.
Objective: to analyze the possible causes and mechanisms of pre-eclampsia.
Materials and methods. Review of the scientific publications in the international electronic scientometric databases PubMed, Embase and Scopus by keywords for a period of 7 years (2011-2017) and comparison of the obtained data with the results of own studies dedicated to the microhemocirculatory bed of the placenta (supravital contact microscopy) and the uterine cervix (lifetime contact microscopy) in pre-eclampsia (Reichert contact colpomicroscope (Austria).
Results. The endoplasmic reticulum stress (ER stress) in pre-eclampsia results from ischemia and reperfusion accompanied by the endometrial pathology of spiral arteries, which in turn is caused by insufficient gestational conversion due to incomplete trophoblast invasion. The ER stress of the syncytiotrophoblast synthesizes a wide range of growth factors, both proangiogenic (the placental and vascular endothelial growth proteins) and antiangiogenic (soluble FMS-like tyrosine kinase and endoglin). An imbalance of these factors leads to the endothelial dysfunction. When the endothelial cells are damaged, antiangiogenic proteins are released. They bind the vascular endothelial growth factor and induce defective gestational remodeling of spiral arteries. Therefore, the changes, which occur in the uterine vascular bed, are most likely to result in the fetal growth restriction as the intensity of blood flow slows down and the fetus experiences ischemia and hypoxia. In response to the changes in the placental-fetal complex, the activation of the release of vasoactive amines into the intervillous space with further invasion into the microcirculatory blood flow in the uterus is observed. We managed to prolong pregnancy and reduce the severity of pre-eclampsia by removing soluble FMS-like tyrosine kinase-1 (antiangiogenic factor) due to extracorporeal apheresis. It is conceivable that pre-eclampsia can be linked to the increased inflammatory response: circulating tumor necrosis factor and interleukin levels are increased in pre-eclampsia.
Conclusions. The criteria for predicting pre-eclampsia include an increase in the levels of α-fetoprotein and inhibin in the maternal blood, podocyturia, the ratio of the proangiogenic growth factor of the placenta PlGF to the antiangiogenic factor of endoglin in combination with measurements of the uterine artery pulsatility index.
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Agostinis, C., R. Bulla, C. Tripodo, C. Guarnotta, F. De Seta, M. Tonon, P. Spessotto, M. Botto i F. Tedesco. "Preeclampsia is associated with defective production of C1q by invasive trophoblast". Molecular Immunology 48, nr 14 (sierpień 2011): 1678–79. http://dx.doi.org/10.1016/j.molimm.2011.06.260.
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Chang, Kai-Jung, Kok-Min Seow i Kuo-Hu Chen. "Preeclampsia: Recent Advances in Predicting, Preventing, and Managing the Maternal and Fetal Life-Threatening Condition". International Journal of Environmental Research and Public Health 20, nr 4 (8.02.2023): 2994. http://dx.doi.org/10.3390/ijerph20042994.
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Preeclampsia accounts for one of the most common documented gestational complications, with a prevalence of approximately 2 to 15% of all pregnancies. Defined as gestational hypertension after 20 weeks of pregnancy and coexisting proteinuria or generalized edema, and certain forms of organ damage, it is life-threatening for both the mother and the fetus, in terms of increasing the rate of mortality and morbidity. Preeclamptic pregnancies are strongly associated with significantly higher medical costs. The maternal costs are related to the extra utility of the healthcare system, more resources used during hospitalization, and likely more surgical spending due to an elevated rate of cesarean deliveries. The infant costs also contribute to a large percentage of the expenses as the babies are prone to preterm deliveries and relevant or causative adverse events. Preeclampsia imposes a considerable financial burden on our societies. It is important for healthcare providers and policy-makers to recognize this phenomenon and allocate enough economic budgets and medical and social resources accordingly. The true cellular and molecular mechanisms underlying preeclampsia remain largely unexplained, which is assumed to be a two-stage process of impaired uteroplacental perfusion with or without prior defective trophoblast invasion (stage 1), followed by general endothelial dysfunction and vascular inflammation that lead to systemic organ damages (stage 2). Risk factors for preeclampsia including race, advanced maternal age, obesity, nulliparity, multi-fetal pregnancy, and co-existing medical disorders, can serve as warnings or markers that call for enhanced surveillance of maternal and fetal well-being. Doppler ultrasonography and biomarkers including the mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), and serum pregnancy-associated plasma protein A (PAPP-A) can be used for the prediction of preeclampsia. For women perceived as high-risk individuals for developing preeclampsia, the administration of low-dose aspirin on a daily basis since early pregnancy has proven to be the most effective way to prevent preeclampsia. For preeclamptic females, relevant information, counseling, and suggestions should be provided to facilitate timely intervention or specialty referral. In pregnancies complicated with preeclampsia, closer monitoring and antepartum surveillance including the Doppler ultrasound blood flow study, biophysical profile, non-stress test, and oxytocin challenge test can be arranged. If the results are unfavorable, early intervention and aggressive therapy should be considered. Affected females should have access to higher levels of obstetric units and neonatal institutes. Before, during, and after delivery, monitoring and preparation should be intensified for affected gravidas to avoid serious complications of preeclampsia. In severe cases, delivery of the fetus and the placenta is the ultimate solution to treat preeclampsia. The current review is a summary of recent advances regarding the knowledge of preeclampsia. However, the detailed etiology, pathophysiology, and effect of preeclampsia seem complicated, and further research to address the primary etiology and pathophysiology underlying the clinical manifestations and outcomes is warranted.
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Singh, Santosh Kumar, i Priti Mishra. "Doppler study of umbilical and fetal middle cerebral artery in severe preeclampsia and intra uterine growth restriction and correlation with perinatal outcome". International Journal of Reproduction, Contraception, Obstetrics and Gynecology 6, nr 10 (23.09.2017): 4561. http://dx.doi.org/10.18203/2320-1770.ijrcog20174442.
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Background: Pre-eclampsia and IUGR are two conditions resulting from defective trophoblastic invasion of spiral arteries and an increase in vascular resistance in uteroplacental circulation. Doppler offers a non-invasive tool for evaluation of fetoplacental blood flow and correlate with fetal compromise giving early warning sign of fetal distress.Methods: The study was conducted in Command Hospital, Lucknow in 100 singleton pregnancies with vertex presentation between 28-40 weeks of gestation with severe preeclampsia and/or IUGR. Doppler analysis of UA and MCA was done. Pregnancies were terminated depending on clinical condition and Doppler results.Results: Abnormal Umbilical artery S/D ratio had strong statistical correlation with poor perinatal outcome. Elevated RI had 100% sensitivity in predicting APGAR<7 at 5 minutes. Elevated PI values was statistically significant in all parameters (except NICU stay>48hrs) in predicting poor perinatal outcome. PI values had highest sensitivity for predicting low APGAR values and highest specificity for predicting NICU admission. AEDF and REDF also correlated with adverse perinatal outcome. MCA S/D ratio had a high sensitivity (96.8%) in determining NICU stay>48h and specificity (70%) in determining NICU admissions. RI had highest sensitivity (71.8%) for NICU stay >48hrs and highest specificity for predicting NICU admissions (76.5%). MCA PI had a sensitivity of 66.6% in determining APGAR<7 at 5min and a specificity of 78.7% in determining NICU admissions. CPR had the highest sensitivity (100%) among all indices.Conclusions: The study showed an adverse fetal outcome in cases of severe preeclampsia and or IUGR which showed abnormal Doppler results and thereby help to determine the optimal time for delivery.
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Suliman, Naglaa Abdelbasit, Khidir Elamin Awadalla, Khalid Hussein Bakheit i Abdelrahim Osman Mohamed. "Cancer antigen 125 and C-reactive protein inflammatory mediators and uric acid in association with preeclampsia in North Kordofan State, Western Sudan". PLOS ONE 18, nr 1 (23.01.2023): e0280256. http://dx.doi.org/10.1371/journal.pone.0280256.
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Pathophysiology of pre-eclampsia depends on a defective trophoblastic invasion of uteroplacental blood vessels that leads to placental ischemia and induction of an inflammatory process within the placenta. This process may trigger the expression of Cancer antigen 125 (CA 125), C-reactive protein (CRP) and uric acid (UA). This research aimed to evaluate the association of serum CA 125, CRP and uric acid with Preeclampsia. The study recruited 200 singleton Sudanese pregnant women, who were divided into three groups: controls (n = 100), mild preeclampsia (n = 46) and severe preeclampsia (n = 54). The study subjects were matched for maternal age, gestational age and body mass index. Blood samples were taken for measurement of the different variables using immune- assay and enzymatic automated chemical analysis. The levels of CA 125 in mild and severe preeclampsia were (21.94±0.749 IU/ml) and (40.78±1.336 IU/ml) respectively, which was significantly different (P<0.001) from the control mean (16.48±0.584 IU/ml). There was also a significant difference between the mean levels of CRP in mild and severe preeclampsia (15.17±0.788 mg/L), (31.50±1.709 mg/L) compared with controls (4.79±0.178 mg/L), (P<0.01). There was also a significant difference in the mean levels of UA in mild and severe cases (6.44±0.293 and7.37±0.272) in comparison with the controls (4.00±0.061); (P<0.001). There were significant differences between severe and mild groups (P<0.05). Cancer antigen 125, CRP and UA levels correlated positively with mean arterial blood pressure (MAP) where (r >0.7; P < 0.001). ROC curve validates the utility of these biomarkers for monitoring preeclampsia (AUC >0.8; P < 0.001). In conclusion CA 125, CRP and UA were significantly higher in preeclampsia compared with the controls. The rise of the analytes was directly associated with the severity of the disease.
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"528B Defective trophoblast invasion in ?lupus? anticoagulant patients". American Journal of Obstetrics and Gynecology 164, nr 1 (styczeń 1991): 391. http://dx.doi.org/10.1016/0002-9378(91)91266-y.
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Valbuena-Diez, Ana Cristina, Jenny Sones, Scott Butler i Robin Davisson. "Abstract 128: Role of Hypoxia-dependent Autophagy in the Trophoblast of BPH/5, a Mouse Model of Pre-eclampsia (PE)". Hypertension 66, suppl_1 (wrzesień 2015). http://dx.doi.org/10.1161/hyp.66.suppl_1.128.
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Autophagy, a mechanism of cell survival, plays an important role in normal placentation and protects the fetus during stress. Previously, we showed that autophagy was increased in fetoplacental units (FPUs) from pregnant BPH/5 mice, a model that develops a PE-like syndrome including late-gestational hypertension, proteinuria, abnormal placentation and poor feto-placental outcomes. We also showed that increased autophagy led to reduced invasion capacity of BPH/5 trophoblasts. Evidence suggests that hypoxia increase autophagy, so we measured the invasion capacity of trophoblasts isolated from C57 mice in normoxic/hypoxic conditions. Trophoblasts cultured in hypoxia exhibited defective invasion, effect partially blocked by autophagy inhibitor chloroquine diphosphate (CQ; 1.7-fold decrease, n=4 p<0.005 hypoxia vs. normoxia; 1.35-fold increase p<0.5 CQ vs. hypoxia). We also tested the effect of conditioned media from BPH/5 or C57 placental explants on the invasion capacity of JAR cells, a human choriocarcinoma trophoblast cell line. Conditioned media from BPH5 explants decreased JAR invasion, but only for 24h after placental collection (1.8-fold decrease, n=4 p<0.005 vs. C571.33-fold p<0.05 vs. BPH/5). However, when the explants were kept in hypoxia, JAR invasion capacity decreased following treatment with BPH5 explants conditioned media, even after 48h; effect partially inhibited by CQ (1.6-fold decrease, n=4 p<0.005 vs. CTR; 1.7-fold, n=4 p<0.05 vs. BPH/5). As autophagy plays a key role in the invasion of trophoblasts and thus remodeling of uterine arteries, we performed a tube formation assay with endothelial cells treated with conditioned media from BPH/5 or C57 placental explants. Tube formation decreased after treatment with conditioned media from BPH/5 explants (1.7-fold decrease, n=3 p<0.05). Co-culture of endothelial and trophoblast cells under hypoxia resulted in less efficient tube formation. Treatment with CQ partially blocked this effect (1.55-fold decrease, n=3 p<0.05 vs normoxia; 1.2-fold, n=3 p<0.05 vs hypoxia). These data demonstrate that invasion capacity and tube formation are defective in trophoblasts from BPH/5 mice, suggesting that hypoxia-dependent autophagy may play a causal role in PE in the BPH/5 model.
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Sang, Yifei, Yanhong Li, Ling Xu, Jiajia Chen, Dajin Li i Meirong Du. "Dysfunction of CCR1+ decidual macrophages is a potential risk factor in the occurrence of unexplained recurrent pregnancy loss". Frontiers in Immunology 13 (2.12.2022). http://dx.doi.org/10.3389/fimmu.2022.1045532.
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Recurrent pregnancy loss (RPL) puzzles 1–3% of women of childbearing age worldwide. Immunological factors account for more than 60% of cases of unexplained RPL (URPL); however, the underlying mechanism remains unclear. Here, using single-cell sequencing data and functional experiments with clinical samples, we identified a distinct population of CCR1+ decidual macrophages (dMφ) that were preferentially enriched in the decidua from normal early pregnancies but were substantially decreased in patients with URPL. Specific gene signatures endowed CCR1+ dMφ with immunosuppressive and migration-regulatory properties, which were attenuated in URPL. Additionally, CCR1+ dMφ promoted epithelial-to-mesenchymal transition (EMT) to promote trophoblast migration and invasion by activating the ERK1/2 signaling pathway. Decidual stromal cell (DSC)-derived CCL8 was the key regulator of CCR1+ dMφ as CCL8 recruited peripheral CCR1+ monocytes, induced a CCR1+ dMφ-like phenotype, and reinforced the CCR1+ dMφ-exerted modulation of trophoblasts. In patients with URPL, CCL8 expression in DSCs was decreased and trophoblast EMT was defective. Our findings revealed that CCR1+ dMφ play an important role in immune tolerance and trophoblast functions at the maternal–fetal interface. Additionally, decreased quantity and dysregulated function of CCR1+ dMφ result in URPL. In conclusion, we provide insights into the crosstalk between CCR1+ dMφ, trophoblasts, and DSCs at the maternal–fetal interface and macrophage-targeted interventions of URPL.
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Deryabin, P. I., J. S. Ivanova i A. V. Borodkina. "Senescent endometrial stromal cells transmit reactive oxygen species to the trophoblast-like cells and impair spreading of blastocyst-like spheroids". Molecular Human Reproduction, 12.11.2022. http://dx.doi.org/10.1093/molehr/gaac039.
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Abstract Successful implantation requires a fine-tuned dialog between the invading embryo and the maternal endometrium. Recently we discovered that premature senescence of endometrial stromal cells (EnSC) might mediate improper decidual transformation of endometrial tissue and impair endometrial-blastocyst interaction. Here we show that senescent EnSC are characterized by elevated intracellular reactive oxygen species (ROS) levels that originate from mitochondrial dysfunction and insufficient antioxidant defense. Decidualization of senescent EnSC is defective and is accompanied by the elevated intracellular and mitochondrial ROS levels . Antioxidant defense during decidualization is significantly less efficient in senescent EnSC compared to healthy ones. Senescent EnSC secrete increased amounts of ROS into the extracellular space. Elevated ROS released by senescent EnSC shift the redox balance and induce DNA damage in the neighbouring trophoblast-like cells. In an in vitro implantation model we observed impaired spreading of blastocyst-like spheroids into a monolayer of decidualizing senescent EnSC, that could be compensated by pretreatment of the senescent cells with the antioxidant Tempol. Hence we propose a possible mechanism that might be responsible at least in part for the defective embryo implantation realized via ROS transmitting from senescent EnSC to trophoblast cells. Such transmission results in accumulation of ROS and subsequent DNA damage in trophoblastic cells what might lead to improper migration and invasion of an embryo. In light of these findings application of antioxidants prior to implantation might be a promising strategy to improve implantation efficiency.
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Yaghoobi, Alireza, Yasaman Nazerian, Arman Zeinaddini Meymand, Ali Ansari, Amirhossein Nazerian i Hassan Niknejad. "Hypoxia-sensitive miRNA regulation via CRISPR/dCas9 loaded in hybrid exosomes: A novel strategy to improve embryo implantation and prevent placental insufficiency during pregnancy". Frontiers in Cell and Developmental Biology 10 (10.01.2023). http://dx.doi.org/10.3389/fcell.2022.1082657.
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Assisted reproductive techniques as a new regenerative medicine approach have significantly contributed to solving infertility problems that affect approximately 15% of couples worldwide. However, the success rate of an in vitro fertilization (IVF) cycle remains only about 20%–30%, and 75% of these losses are due to implantation failure (the crucial rate-limiting step of gestation). Implantation failure and abnormal placenta formation are mainly caused by defective adhesion, invasion, and angiogenesis. Placental insufficiency endangers both the mother’s and the fetus’s health. Therefore, we suggested a novel treatment strategy to improve endometrial receptivity and implantation success rate. In this strategy, regulating mir-30d expression as an upstream transcriptomic modifier of the embryo implantation results in modified expression of the involved genes in embryonic adhesion, invasion, and angiogenesis and consequently impedes implantation failure. For this purpose, “scaffold/matrix attachment regions (S/MARs)” are employed as non-viral episomal vectors, transfecting into trophoblasts by exosome-liposome hybrid carriers. These vectors comprise CRISPR/dCas9 with a guide RNA to exclusively induce miR-30d gene expression in hypoxic stress conditions. In order to avoid concerns about the fetus’s genetic manipulation, our vector would be transfected specifically into the trophoblast layer of the blastocyst via binding to trophoblast Erb-B4 receptors without entering the inner cell mass. Additionally, S/MAR episomal vectors do not integrate with the original cell DNA. As an on/off regulatory switch, a hypoxia-sensitive promoter (HRE) is localized upstream of dCas9. The miR-30d expression increases before and during the implantation and placental insufficiency conditions and is extinguished after hypoxia elimination. This hypothesis emphasizes that improving the adhesion, invasion, and angiogenesis in the uterine microenvironment during pregnancy will result in increased implantation success and reduced placental insufficiency, as a new insight in translational medicine.
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Lee, Solji, Jiha Shin, Yeji Hong, Seong Min Shin, Hye Won Shin, Jongdae Shin, Sung Ki Lee i Hwan‐Woo Park. "Sestrin2 alleviates palmitate‐induced endoplasmic reticulum stress, apoptosis, and defective invasion of human trophoblast cells". American Journal of Reproductive Immunology 83, nr 4 (5.02.2020). http://dx.doi.org/10.1111/aji.13222.
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Oudejans, Cees, Vera Manders, Allerdien Visser, Remco Keijser, Naomi Min, Ankie Poutsma, Joyce Mulders i in. "Circular RNA Sequencing of Maternal Platelets: A Novel Tool for the Identification of Pregnancy-Specific Biomarkers". Clinical Chemistry, 30.11.2020. http://dx.doi.org/10.1093/clinchem/hvaa249.
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Abstract Background In the first trimester of pregnancy, the maternal platelet is directly involved in a positive feedback mechanism that facilitates invasion of the extravillous trophoblast into the maternal spiral arteries. Dysfunctional trophoblast invasion with defective deep placentation is primordial in the etiology of the “great obstetrical syndromes.” Methods In this proof-of-concept study, using transcriptome analysis of circular RNA (circRNA) following RNA sequencing of maternal platelets, we tested whether pregnancy-specific circRNA markers could be identified in the first trimester of normal pregnancies. Differential transcript expression analysis of circRNAs, as predicted by Accurate CircRNA Finder Suite, CircRNA Identifier (version 2), and Known and Novel Isoform Explorer, was done using thromboSeq.R with variation of multiple settings. Test performance was checked for (a) de novo circRNA identification using the novel platelet-specific Plt-circR4 as a positive control, (b) complete segregation of groups (pregnant vs nonpregnant) after heat map–dendrogram clustering, (c) identification of pregnancy-specific circRNA markers at a false discovery rate (FDR) <0.05, and (d) confirmation of differentially expressed circRNA markers with an FDR <0.05 by an independent method, reverse transcription–quantitative PCR. Results Of the differentially expressed circRNAs with P values <0.05, 41 circRNAs were upregulated (logFC >2), and 52 circRNAs were downregulated (logFC less than −2) in first-trimester platelet RNA. Of these, nuclear receptor-interacting protein 1 circRNA covering exons 2 and 3 of the 5′-untranslated region was pregnancy specific with upregulation in first-trimester maternal platelets compared to nonpregnant controls. Conclusion CircRNA sequencing of first-trimester maternal platelets permits the identification of novel pregnancy-specific RNA biomarkers. Future use could include the assessment of maternal and fetal well-being.
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Ruikar, Komal, Manjunatha Aithala, Praveenkumar Shetty, Udupi Shastry Dinesh, Anil Bargale, Roshni Sadashiv, Sarathkumar Edachery veedu, Vitthal Khode, Asha Neravi i Prakash Patil. "Decreased expression of annexin A2 and loss of its association with vascular endothelial growth factor leads to the deficient trophoblastic invasion in preeclampsia". Journal of Basic and Clinical Physiology and Pharmacology, 21.04.2021. http://dx.doi.org/10.1515/jbcpp-2020-0321.
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Abstract Objectives Preeclampsia (PE) remains the major cause for maternal and foetal mortality and morbidity. Invasion of endovascular trophoblast and remodelling of spiral artery are crucial actions of normal placental development. Non-fulfilment of these processes plays a leading role in the development of preeclampsia. Vascular endothelial growth factor (VEGF) is produced by extravillous trophoblastic tissue and decidual cell population is a well-known angiogenic growth which plays a fundamental role in placental pathogenesis of PE. Annexin A2 (ANXA2) is a profibrinolytic protein receptor required for plasminolysis, which is an important step in the formation of new blood vessel along with VEGF. Role of ANXA2 is poorly studied in context with human reproductive disease like preeclampsia. The purpose of the present study is to examine the expression and association of VEGF and ANXA2 in the term placentas of pregnancies with and without PE. Methods The study group comprised of placental tissues procured from gestations with PE (n=30) and without (n=20) PE. The expression of VEGF and ANXA2 in the placental villous tissue was evaluated quantitatively by means of IHC, western blotting and reverse transcriptase-polymerase chain reaction (RT-PCR). Results Our IHC, western blotting and RT-PCR analysis illustrated the significant decrease in the expression of VEGF and ANXA2 in PE group compared with the normotensive control group (p<0.005). We observed statistically significant positive correlation among the expression of ANXA2 and VEGF in placentas of normotensive control group (p<0.0001). Conclusions The diminished expression of VEGF and ANXA2 in placenta may be associated with the defective angiogenesis and which may possibly play a vital role in PE pathogenesis.
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Sandgren, Jeremy A., Katherine N. Gibson-Corley, Danny W. Linggonegoro, Katherine J. Perschbacher, Shao Yang Zhang, Sabrina M. Scroggins, Guorui Deng i in. "Abstract P256: Vasopressin Infusion During Pregnancy in Mice Induces Early Histological Placental Phenotypes of Preeclampsia". Hypertension 70, suppl_1 (wrzesień 2017). http://dx.doi.org/10.1161/hyp.70.suppl_1.p256.
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Human preeclampsia (PE) is associated with elevated secretion of arginine vasopressin (AVP), and chronic infusion of AVP into pregnant mice is sufficient to model PE by causing hypertension, renal glomerular endotheliosis, proteinuria, fetal placental hypoxia, and growth restriction. Early stages of PE are associated with defective trophoblast invasion of maternal spiral arteries, leading to decreased artery diameter and placental oxygenation. AVP infusion (24 ng/hr, sc) into pregnant mice caused placental hypoxia (chromatin-bound HIF1α on gestational day (GD)17.5; saline n=5, 0.31±0.01; AVP n=5, 0.34±0.01 AU, p<0.05) and reduced placental growth factor mRNA (n=18, 1.0 (0.7-1.3) vs n=21, 0.3 (0.2-0.4) fold (1 se), p<0.05). Therefore, we performed histological analyses of placentas collected from mice at GD12.5 infused with saline or AVP, with the hypothesis that AVP leads to early placental PE phenotypes. Similar to effects on GD17.5, this preliminary cohort demonstrated increased urine protein content (n=7, 27±3 vs n=13, 44±3, g/L p<0.05) and mid-gestational systolic blood pressure (-7.6±3.1 vs +3.5±2.2, mmHg p<0.05), similar fetal (75±7 vs 78±4 mg, p=0.75) and placental (83±10 vs 81±4 mg, p=0.80) masses, and similar changes in heart rate (+37±16 vs +39±12 bpm, p=0.93). GD12.5 placentas were then stained with haemotoxylin and eosin or immunostained for cytokeratin-8 to examine morphological changes induced by AVP. AVP infusion had no significant effects on labyrinth (saline n=3, 647±25 vs AVP n=7, 602±35 um, p=0.45), spongiotrophoblast (342±19 vs 363±24 um, p=0.61), or decidua (622±47 vs 520±47 um, p=0.24) layer thicknesses. AVP caused a reduction in average maximum spiral artery diameter (171±28 vs 121±8 um, p<0.05) and a trend toward reduced total spiral artery number (8.4±2.9 vs 4.9±0.7, p=0.13), but no difference in the maximum invasion depth of CK8-positive trophoblasts (310±50 vs 286±37 um, p=0.72). We conclude that AVP infusion is sufficient to induce cardinal mid-gestational features of PE in pregnant mice, including reduced spiral artery diameter. Such morphological changes may be associated with the placental hypoxia and reduced placental growth factor expression in model.
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Sinha, Nivedita, Alpana Singh, BD Banerjee, Rachna Agarwal i Himsweta Srivastva. "Maternal Pregnancy Associated Plasma Protein-A Levels in Late First Trimester as a Predictor of Miscarriage- A Cross-sectional Study". JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH, 2021. http://dx.doi.org/10.7860/jcdr/2021/50626.15444.
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Indroduction: Miscarriage is the most common complication of pregnancy. Defective implantation is one of the common causes of miscarriage. Pregnancy Associated Plasma Protein-A (PAPP-A) is secreted from syncytiotrophoblast and it enables trophoblast invasion. Few studies have shown association of PAPP-A with miscarriage. However, there is limited data available to establish the role of PAPP-A as a predictive marker of miscarriage, especially in Indian population. Aim: To determine the potential of maternal PAPP-A level estimation in asymptomatic women in late first trimester (10-13 weeks) with viable foetus in predicting subsequent miscarriage. Materials and Methods: This was an observational, cross-sectional study conducted from November 2016 to April 2018 at University College of Medical Science and Guru Teg Bahadur Hospital, Delhi, India. Asymptomatic pregnant women (N=500) at 10-13 weeks of gestation were recruited from an antenatal clinic after confirmation of foetal viability. A 2 mL of blood sample was collected and serum PAPP-A level was measured. Independent t-test and Chi-square test was used to compare continuous data and Mann-Whitney U test was used to compare PAPP-A Multiple of Median (MOM). Logistic regression was used to estimate risk of miscarriage. Results: Out of 500 participants, 9 were lost to follow-up. From remaining N=491, 32 (6.5%) women had a miscarriage. PAPP-A levels were significantly decreased in miscarriage group compared to ongoing pregnancy group with median MOM 0.116 (0.080-0.17) and 1.25 (0.665-3.249) respectively (p-value <0.001). PAPP-A MOM value of ≤10th percentile sensitivity and specificity of detection of miscarriage was 81.25% and 94.98% and at ≤5th percentile sensitivity and specificity was 40.62% and 97.82%, respectively. Lower the percentile cut-off of serum PAPP-A value, higher was the specificity and positive predictive value for prediction of miscarriage. By applying logistic regression we found that if PAPP-A MOM decreases by 1 unit the chances of miscarriage increased by 1.2 times. By this model 63.2% of cases could be explained (Nagelkerke R Square=0.632). For prediction of pregnancies likely to miscarry, the area under Receiver Operator Characteristic (ROC) curve (95% CI) was 0.969 (0.955-0.983). Conclusion: Low serum PAPP-A levels from asymptomatic women in late 1st trimester is a good predictive marker of miscarriage.
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Valbuena-Diez, Ana Cristina, Jenny L. Sones, Scott D. Butler, Unisha Patel i Robin L. Davisson. "Abstract 287: Evidence For Increased Autophagy In Fetoplacental Units Of Bph/5, A Mouse Model Of Pre-eclampsia (PE)". Hypertension 64, suppl_1 (wrzesień 2014). http://dx.doi.org/10.1161/hyp.64.suppl_1.287.
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Autophagy, a mechanism of cell survival during times of stress, plays an important role in normal placentation, protecting the fetus during fluctuations in conditions such as nutrient availability. In cases of placental insufficiency, often present in PE, autophagy may be defective. We have shown that BPH/5 mice, in addition to spontaneously developing a PE-like syndrome including late-gestational hypertension and proteinuria, exhibit abnormal placentation and poor feto-placental outcomes. Here we tested the hypothesis that there is increased autophagy in fetoplacental units (FPUs) of pregnant BPH/5 females. RNA was extracted from FPUs (e10.5) of BPH/5 and C57 control mice and analyzed for biomarkers of autophagy. BPH/5 showed a significant increase in both Beclin-1 and LC3-β compared to C57 (1.5-fold for each, n=7; p<0.05). Increased autophagy in e10.5 BPH/5 FPUs was corroborated at the protein level using ELISA to measure Beclin-1 (0.6±0.1 control vs. 2±0.17 ng/mL BPH/5; n=7; p<0.05). We also analyzed protein levels of p62, an autophagy biomarker which is degraded during autophagy. Consistent with these other findings, the levels of p62 were lower in BPH/5 mice (29.7±2.5 controls vs. 7.2±1.3 ng/mL BPH/5, p<0.05). Given that autophagy in trophoblasts plays a key role in the invasion of these cells and thus remodeling of uterine arteries, we examined the invasion capacity of e10.5 trophoblasts isolated from C57 and BPH/5 mice. Trophoblasts from BPH/5 mice were much less invasive when compared to C57 (2-fold decrease, n=7; p<0.05). Inhibition of autophagy with chloroquine diphosphate (50 μM) significantly improved invasion capacity of these cells (1.6-fold increase; n=7; p<0.05). Collectively, these data demonstrate that autophagy is defective in FPUs from BPH/5 mice, and suggest that this may play a causal role in PE in this model.
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"Placenta Accreta Spectrum: A preventable nearly iatrogenic disorder." JUNIOR MEDICAL RESEARCH, 30.05.2021, 24–25. http://dx.doi.org/10.32512/jmr.3.2.2020/24.25.
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Placenta accreta spectrum (PAS) refers to the range of pathologic adherence of the placenta, including placenta increta, placenta percreta, and placenta accreta. PAS disorder is a maternal and fetal life-threatening situation due to the high risk of intrapartum uncontrollable bleeding. The common described risk factors are the placenta previa and history of Caesarean section (CS) [1]. We herein report our experience with five patients referred to our department for suspected PAS. These patient were selected for targeted prepartum ultrasound assessment due to their history of multiple C-sections. PAS risk increase with the number of previous CS and could reach7% [2]. In Nicaragua , the rate of c-section in obstetrical practice is still high and approximating 40% in some centers. Uterine wall dehiscence result in locally defective decidualisation and abnormal placental adherence with important trophoblastic invasion in a subsequent pregnancy [3]. We still believe that this disorder is preventable if we “go back” a little to obstetrical good practices. Dramatic situations can be avoided by selecting suspected PAS on ultrasound or MRI to be referred. PAS is the commonest cause of intrapartum hysterectomy and must be managed always in specialized centers with multidisciplinary team approach.
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Mecacci, F., L. Avagliano, F. Lisi, S. Clemenza, Caterina Serena, S. Vannuccini, M. P. Rambaldi, S. Simeone, S. Ottanelli i F. Petraglia. "Fetal Growth Restriction: Does an Integrated Maternal Hemodynamic-Placental Model Fit Better?" Reproductive Sciences, 19.11.2020. http://dx.doi.org/10.1007/s43032-020-00393-2.
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AbstractIn recent years, a growing interest has arisen regarding the possible relationship between adverse pregnancy outcomes (APOs) and inadequate maternal hemodynamic adaptations to the pregnancy. A possible association between “placental syndromes,” such as preeclampsia (PE) and fetal growth restriction (FGR), and subsequent maternal cardiovascular diseases (CVD) later in life has been reported. The two subtypes of FGR show different pathogenetic and clinical features. Defective placentation, due to a poor trophoblastic invasion of the maternal spiral arteries, is believed to play a central role in the pathogenesis of early-onset PE and FGR. Since placental functioning is dependent on the maternal cardiovascular system, a pre-existent or subsequent cardiovascular impairment may play a key role in the pathogenesis of early-onset FGR. Late FGR does not seem to be determined by a primary abnormal placentation in the first trimester. The pathological pathway of late-onset FGR may be due to a primary maternal cardiovascular maladaptation: CV system shows a flat profile and remains similar to those of non-pregnant women. Since the second trimester, when the placenta is already developed and increases its functional request, a hypovolemic state could lead to placental hypoperfusion and to an altered maturation of the placental villous tree and therefore to an altered fetal growth. Thus, this review focalizes on the possible relationship between maternal cardiac function and placentation in the development of both early and late-onset FGR. A better understanding of maternal hemodynamics in pregnancies complicated by FGR could bring various benefits in clinical practice, improving screening and therapeutic tools.
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Suliman, Naglaa Abdelbasit, Khidir Elamin Awadalla, Khalid Hussein Bakheit i Abdelrahim Osman Mohamed. "Inflammatory Mediators (CA125, CRP) and Uric Acid in Association with Severity of Preeclampsia in North Kordofan State, Western Sudan". International Journal of Biochemistry Research & Review, 4.11.2022, 1–10. http://dx.doi.org/10.9734/ijbcrr/2022/v31i10781.
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Introduction: Inflammatory mediators could be laboratory markers of preeclampsia, as the induction of an inflammatory process within the placenta may trigger the expression of cancer antigen 125(CA125), C-reactive protein (CRP) and uric acid (UA). Regarding the pathophysiology of pre-eclampsia, there is defective trophoblastic invasion of uteroplacental blood vessels that leads to placental ischemia, and induction of an inflammatory process within the placenta.
Objective: To evaluate the association of serum levels of cancer antigen (CA125), C-reactive protein (CRP) and serum uric acid with the Severity of Preeclampsia.
Materials and Methods: The study recruited 200 singleton Sudanese pregnant women. These participants were divided into two groups: control (n = 100) and cases (n = 100). The cases were further subdivided into; mild preeclampsia (n =46), and severe preeclampsia (n = 54). The study groups were well-matched in maternal age, gestational age and body mass index. Blood samples were taken for measurement of serum cancer antigen-CA125, uric acid and C - reactive protein using immune- assay and enzymatic automated chemical analysis.
Results: The mean levels of cancer antigen-CA125 in mild and severe preeclampsia groups were; 21.94±5.08 (IU/ml) and 40.77±9.82 (IU/ml) respectively, which were significantly higher, (P<0.001) in comparison with the control group (16.88±7.36 (IU/ml). The mean levels of C-reactive protein in mild and severe preeclampsia were; 15.17±5.35 (mg/L), 31.49±12.56 (mg/L) respectively. There was significant difference in their levels, compared to the control group (4.79±1.78 (mg/L), (P<0.01). Also, the mean levels of uric acid in mild and severe cases were; 6.44±1.98 and 7.37±2.00 which was significantly higher, in comparison with the control (4.00±0.61); (P<0.001). The level of uric acid also, showed significant difference within the case (severe and mild) group (P<0.05). CA125, CRP and UA levels correlated positively with Mean Arterial blood pressure (MAP), (r>0.7; P < 0.001). ROC curve validate the utility of these biomarker for the detection of preeclampsia severity (AUC>0. 8; P < 0.001).
Conclusion: Serum cancer antigen 125(CA125), C- reactive protein and uric acid in studied preeclampsia groups were found to be significantly higher compared with the control group, and the rises were directly associated with the severity of preeclampsia.
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Olumodeji, Ayokunle Moses, Olumide Emmanuel Adewara, Olabisi Timothy Adeyemo, Segun Murtala Ghazali i Paul Olowoyo. "Alpha Fetoprotein as a Marker of Severe Disease and Foetal Outcome in Pregnancy Induced Hypertension". International Journal of Innovative Research in Medical Science 4, nr 03 (11.03.2019). http://dx.doi.org/10.23958/ijirms/vol04-i03/599.
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Background: Pregnancy-induced hypertension represents the most common medical complication of pregnancy and contributes significantly to maternal and neonatal morbidity and mortality. Many theories have been implicated in its genesis, crucial among which is the defective 2nd wave of trophoblastic invasion/placentation. Maternal serum alpha fetoprotein is a marker of placental abnormalities and may correlate with clinical features of significant management implications. This study evaluated the role of maternal Alpha-fetoprotein concentration as a marker of disease severity and foetal outcome in patients with pregnancy induced hypertension at the Federal Teaching Hospital, Ido-Ekiti, Ekiti state, Nigeria. Methodology: This was a prospective study in which 44 patients with PIH and 88 matched controls that satisfied the inclusion criteria were recruited using convenience sampling technique for cases and systematic random sampling for controls. Relevant socio-demographic, maternal medical and obstetric characteristics, alpha-fetoprotein levels and fetal outcome measures were obtained. A p-value of less than 0.05 was considered statistically significant. SPSS 20.0 statistical package (SPSS Inc, Chicago, IL, USA) was used for statistical analysis. Results: The prevalence of PIH in the study was 15.3%. The difference in the mean (±2SD) serum level of alpha fetoprotein (AFP) between the cases (207±156.2ng/ml) and control group (165.2±115.1ng/ml) was not statistically significant (p=0.079). The mean (±2SD) birth weight of babies born to women with PIH in this study was 2.7±0.6kg which was significantly lower (p<0.001; 95%CI 3.0 – 3.1)) than the mean birth weights of 3.2±0.4kg of babies of normotensive controls. The mean (± 2SD) Apgar scores at both 1 minute and 5 minutes were both significantly lower in the PIH group (6.7±1.8 and 8.4±1.5 respectively) than among the normotensive women (7.6±1.2 and 8.9±1.1 respectively). Thirty-one point eight percentage of babies born to women in the PIH group and 11.4% of babies of normotensive controls required admission into special care baby unit (SCBU) (Odds Ratio=1.17; 95%CI (0.24-5.76) Serum AFP had a reasonable negative correlation with both birth weight (r=-0.47, p=0.001) and Apgar score at 5 minute (r=-0.44, p=0.002). At 2 MoM serum AFP level, sensitivity and specificity for severe PIH were 36% and 90% respectively. Conclusion: Maternal serum AFP levels showed reasonable positive correlation with disease severity and adverse fetal outcome that warrants further investigation. Maternal serum AFP can be useful in identifying pregnant women with PIH at risk of having severe disease and adverse foetal outcome.
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Al-Lamee, H., N. Tempest, J. Drury, A. Drakeley i D. Hapangama. "P-365 Pre-selected for an award: Altered endometrial oestrogen-responsiveness and aberrant expression of cell-fate markers may contribute to the aetiology of recurrent pregnancy loss". Human Reproduction 36, Supplement_1 (1.07.2021). http://dx.doi.org/10.1093/humrep/deab127.068.
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Abstract Study question Do women with recurrent pregnancy loss (RPL) have an aberrant expression of oestrogen receptor-β (ERβ) and cell-fate markers during the window of implantation (WOI) endometrium? Summary answer Women with RPL are found to have significantly altered levels of ERβ and Ki-67 in the WOI endometrium, possibly resulting in anti-proliferative and anti-angiogenic effects. What is known already RPL affects 1% of all women and has been associated with altered endometrial angiogenesis and proliferation when compared with the endometrium of healthy fertile women. RPL can be subcategorised into recurrent loss of anembryonic pregnancy, fetal loss (following evidence of a fetal heartbeat) and recurrent implantation failure (RIF). ERβ is the only oestrogen-receptor (ER) known to be expressed in the vascular endothelium of the endometrium and is the dominant ER during the WOI. It has an important role in endometrial regeneration and is proposed to regulate the angiogenic and vascular changes that occur in embryo implantation. Study design, size, duration This pilot case-control study took place at the Liverpool Women’s Hospital and included 38 women; 29 who suffered RPL and 9 controls with proven fertility (≥2 healthy pregnancies). Of the RPL group, 9 had recurrent loss of anembryonic pregnancy, 10 had recurrent fetal loss and 10 had RIF. Endometrial samples were collected during the WOI (cycle day 22+/-2). Participants/materials, setting, methods To determine whether markers of endometrial cell proliferation and oestrogen-responsiveness are associated with RPL, we assessed the immuno-staining for ERβ, progesterone receptor (PR) and cell-fate marker Ki-67 in endometrial biopsies during the WOI using immunohistochemistry. A semi-quantitative immuno-staining score was used to assess the endometrial glands, stroma, luminal epithelium, perivascular and vascular endothelium compartments separately. Statistical differences between groups were calculated by non-parametric tests and significance level set at p < 0.05. Main results and the role of chance During the WOI, the endometrial epithelium of women with RIF and recurrent anembryonic pregnancy loss showed significantly higher levels of ERβ when compared with fertile controls (p = 0.01 and p = 0.01, respectively). This may indicate an anti-proliferative process occurring at the site of implantation with very early pregnancy losses. In contrast, with women with recurrent fetal loss, a significantly lower level of ERβ was found within the vascular endothelium when compared with the fertile controls (p < 0.01). This supports the theory that increased oxygen levels may compromise trophoblastic invasion, thereby leading to fetal loss. The presence of Ki-67 (a marker of proliferation) was significantly lower within the vascular endothelium of all types of RPL recurrent anembryonic loss (p = 0.02), RIF (p = 0.02) and recurrent fetal loss (p < 0.01). These findings suggest ineffective endometrial angiogenesis in RPL, resulting in a suboptimal endometrial microenvironment. PR was found to be significantly reduced (p < 0.01) in the perivascular area of women with RIF versus fertile controls. Since decidualisation and preparation of the endometrium for a successful implantation is controlled by critical target genes downstream of PR, this alteration in PR may be an important feature of their defective endometrial phenotype. Limitations, reasons for caution Samples analysed were taken from the functional endometrium and therefore the results do not reflect the basalis. The WOI was identified using history and histological appearance, rather than timing with ovulation. Although we detected statistical significance, generalisation of the results requires further studies with larger sample size. Wider implications of the findings This data provides novel insight into the biological correlates of clinical types of RPL and suggests that specific alterations in the regulation of endometrial cell fate and oestrogen- responsiveness are associated with different types of RPL. This highlights possible new therapies for RPL, such as selective oestrogen receptor modulators (SERMs). Trial registration number Not applicable
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Al-Lamee, H., N. Tempest, J. Drury, A. Drakeley i D. Hapangama. "P–365 Altered endometrial oestrogen-responsiveness and aberrant expression of cell-fate markers may contribute to the aetiology of recurrent pregnancy loss". Human Reproduction 36, Supplement_1 (1.07.2021). http://dx.doi.org/10.1093/humrep/deab130.364.
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Abstract Study question Do women with recurrent pregnancy loss (RPL) have an aberrant expression of oestrogen receptor-β(ERβ) and cell-fate markers during the window of implantation (WOI) endometrium? Summary answer Women with RPL are found to have significantly altered levels of ER βand Ki–67 in the WOI endometrium, possibly resulting in anti-proliferative and anti-angiogenic effects. What is known already RPL affects 1% of all women and has been associated with altered endometrial angiogenesis and proliferation when compared with the endometrium of healthy fertile women. RPL can be subcategorised into recurrent loss of anembryonic pregnancy, fetal loss (following evidence of a fetal heartbeat) and recurrent implantation failure (RIF). ERβis the only oestrogen-receptor (ER) known to be expressed in the vascular endothelium of the endometrium and is the dominant ER during the WOI. It has an important role in endometrial regeneration and is proposed to regulate the angiogenic and vascular changes that occur in embryo implantation. Study design, size, duration: This pilot case-control study took place at the Liverpool Women’s Hospital and included 38 women; 29 who suffered RPL and 9 controls with proven fertility (≥2 healthy pregnancies). Of the RPL group, 9 had recurrent loss of anembryonic pregnancy, 10 had recurrent fetal loss and 10 had RIF. Endometrial samples were collected during the WOI (cycle day 22+/–2). Participants/materials, setting, methods To determine whether markers of endometrial cell proliferation and oestrogen-responsiveness are associated with RPL, we assessed the immuno-staining for ER β, progesterone receptor (PR) and cell-fate marker Ki–67 in endometrial biopsies during the WOI using immunohistochemistry. A semi-quantitative immuno-staining score was used to assess the endometrial glands, stroma, luminal epithelium, perivascular and vascular endothelium compartments separately. Statistical differences between groups were calculated by non-parametric tests and significance level set at p < 0.05. Main results and the role of chance During the WOI, the endometrial epithelium of women with RIF and recurrent anembryonic pregnancy loss showed significantly higher levels of ER βwhen compared with fertile controls (p = 0.01 and p = 0.01, respectively). This may indicate an anti-proliferative process occurring at the site of implantation with very early pregnancy losses. In contrast, with women with recurrent fetal loss, a significantly lower level of ERβwas found within the vascular endothelium when compared with the fertile controls (p < 0.01). This supports the theory that increased oxygen levels may compromise trophoblastic invasion, thereby leading to fetal loss. The presence of Ki–67 (a marker of proliferation) was significantly lower within the vascular endothelium of all types of RPL: recurrent anembryonic loss (p = 0.02), RIF (p = 0.02) and recurrent fetal loss (p < 0.01). These findings suggest ineffective endometrial angiogenesis in RPL, resulting in a suboptimal endometrial microenvironment. PR was found to be significantly reduced (p < 0.01) in the perivascular area of women with RIF versus fertile controls. Since decidualisation and preparation of the endometrium for a successful implantation is controlled by critical target genes downstream of PR, this alteration in PR may be an important feature of their defective endometrial phenotype. Limitations, reasons for caution Samples analysed were taken from the functional endometrium and therefore the results do not reflect the basalis. The WOI was identified using history and histological appearance, rather than timing with ovulation. Although we detected statistical significance, generalisation of the results requires further studies with larger sample size. Wider implications of the findings: This data provides novel insight into the biological correlates of clinical types of RPL and suggests that specific alterations in the regulation of endometrial cell fate and oestrogen- responsiveness are associated with different types of RPL. This highlights possible new therapies for RPL, such as selective oestrogen receptor modulators (SERMs). Trial registration number Not applicable