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Alaca R, Demirci T, Topdaği Yilmaz EP, Öztürk N. Investigation of Urotensin II expression in placenta and umbilical cord in pregnancies with intrauterine growth restriction by histological and biochemical methods. Placenta 2024; 158:1-9. [PMID: 39305699 DOI: 10.1016/j.placenta.2024.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/05/2024] [Accepted: 09/05/2024] [Indexed: 12/11/2024]
Abstract
OBJECTIVE In this study, it was aimed to investigate Urotensin II in intrauterine growth restriction (IUGR) and its connection to autophagy and/or apoptosis in placenta and umbilical cord by immunohistochemical and biochemical methods. MATERIALS AND METHODS The study included 30 healthy pregnant women and 30 pregnant women with IUGR, aged 19-45, at Atatürk University Gynecology Clinic. Samples were collected from placenta, umbilical cord, maternal blood, and umbilical cord blood during delivery. Histopathological examination was carried out on placenta and umbilical cord, and UTII, Beclin 1, and caspase 3 expressions were analyzed in these tissues. Biochemical analysis was performed on maternal and umbilical cord serum samples. RESULTS In healthy placentas, normal villus formation was seen, but those with IUGR showed accelerated villus maturation, causing inadequate nutrition and development. IUGR placentas had fibrin deposition, villous edema, syncytial nodes increase, and intervillous distance. Umbilical cords of IUGR group had differences in vessel wall thickness, arterial lumens, and vessel number. Higher levels of UTII, Beclin 1, and caspase 3 were found in IUGR placenta and cord. Beclin 1 and caspase 3 levels were significantly higher in IUGR group compared to controls, while UTII levels were not significantly different in maternal and cord serums. CONCLUSION As a result of our findings, UTII increase in placenta and umbilical cord may lead to IUGR formation by inducing autophagy and apoptosis.
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Affiliation(s)
- Raziye Alaca
- Erzurum City Hospital, Andrology Labarotory, Erzurum, Turkey
| | - Tuba Demirci
- Ataturk University Faculty of Medicine, Department of Histology and Embryology, Erzurum, Turkey.
| | | | - Nurinnisa Öztürk
- Ataturk University Faculty of Medicine, Department of Medical Biochemistry, Erzurum, Turkey
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Karabay G, Bayraktar B, Seyhanli Z, Tokguz Cakir B, Aktemur G, Topkara Sucu S, Tonyali NV, Ipek S, Kolomuc Gayretli T, Celen S. New Marker in the Umbilical Cord Blood of Fetuses with Fetal Growth Restriction: Serum Sortilin-1 Level. Fetal Pediatr Pathol 2024; 43:466-476. [PMID: 39387812 DOI: 10.1080/15513815.2024.2412846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/01/2024] [Accepted: 09/30/2024] [Indexed: 10/15/2024]
Abstract
Objective: To determine the role of sortilin in the pathogenesis of fetal growth restriction (FGR) by examining serum sortilin levels in fetal cord blood. Methods: This prospective case-control study was conducted at Ankara Etlik City Hospital between July 2023 and January 2024. Group 1 included 44 pregnant women with late FGR; Group 2 included 44 healthy pregnant women as controls. Results: Umbilical cord blood sortilin levels were significantly higher in the FGR group [2.96 (2.43-4.01)] compared to the control group [2.12 (1.74-3.18)] (p = 0.001). Sortilin levels negatively correlated with APGAR scores at 1 min (r=-0.281, p = 0.008) and 5 min (r=-0.292, p = 0.006). A sortilin threshold of 2.58 ng/ml predicted composite adverse neonatal outcomes with 66.7% sensitivity, 53.1% specificity, and an AUC of 0.652 (95% CI: 0.529-0.775, p = 0.031). Conclusion: This study showed that sortilin levels, which are indicators of oxidation, were higher in the cord blood of newborns with late FGR.
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Affiliation(s)
- Gulsan Karabay
- Department of Obstetrics and Gynecology, Division of Perinatology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Burak Bayraktar
- Department of Obstetrics and Gynecology, Division of Perinatology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Zeynep Seyhanli
- Department of Obstetrics and Gynecology, Division of Perinatology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Betul Tokguz Cakir
- Department of Obstetrics and Gynecology, Division of Perinatology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Gizem Aktemur
- Department of Obstetrics and Gynecology, Division of Perinatology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Serap Topkara Sucu
- Department of Obstetrics and Gynecology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Nazan Vanlı Tonyali
- Department of Obstetrics and Gynecology, Division of Perinatology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Selma Ipek
- Department of Obstetrics and Gynecology, Ankara Etlik City Hospital, Ankara, Turkey
| | | | - Sevki Celen
- Department of Obstetrics and Gynecology, Division of Perinatology, Ankara Etlik City Hospital, Ankara, Turkey
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Zhang Y, Li T, Yue CY, Liu Y. Associations of serum D-dimer and glycosylated hemoglobin levels with third-trimester fetal growth restriction in gestational diabetes mellitus. World J Diabetes 2024; 15:914-922. [PMID: 38766442 PMCID: PMC11099364 DOI: 10.4239/wjd.v15.i5.914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/24/2024] [Accepted: 03/15/2024] [Indexed: 05/10/2024] Open
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is a special type of diabetes that commonly occurs in women during pregnancy and involves impaired glucose tolerance and abnormal glucose metabolism; GDM is diagnosed for the first time during pregnancy and can affect fetal growth and development. AIM To investigate the associations of serum D-dimer (D-D) and glycosylated hemoglobin (HbA1c) levels with third-trimester fetal growth restriction (FGR) in GDM patients. METHODS The clinical data of 164 pregnant women who were diagnosed with GDM and delivered at the Obstetrics and Gynecology Hospital of Fudan University from January 2021 to January 2023 were analyzed retrospectively. Among these women, 63 whose fetuses had FGR were included in the FGR group, and 101 women whose fetuses had normal body weights were included in the normal body weight group (normal group). Fasting venous blood samples were collected from the elbow at 28-30 wk gestation and 1-3 d before delivery to measure serum D-D and HbA1c levels for comparative analysis. The diagnostic value of serum D-D and HbA1c levels for FGR was evaluated by receiver operating characteristic analysis, and the influencing factors of third-trimester FGR in GDM patients were analyzed by logistic regression. RESULTS Serum fasting blood glucose, fasting insulin, D-D and HbA1c levels were significantly greater in the FGR group than in the normal group, while the homeostasis model assessment of insulin resistance values were lower (P < 0.05). Regarding the diagnosis of FGR based on serum D-D and HbA1c levels, the areas under the curves (AUCs) were 0.826 and 0.848, the cutoff values were 3.04 mg/L and 5.80%, the sensitivities were 81.0% and 79.4%, and the specificities were 88.1% and 87.1%, respectively. The AUC of serum D-D plus HbA1c levels for diagnosing FGR was 0.928, and the sensitivity and specificity were 84.1% and 91.1%, respectively. High D-D and HbA1c levels were risk factors for third-trimester FGR in GDM patients (P < 0.05). CONCLUSION D-D and HbA1c levels can indicate the occurrence of FGR in GDM patients in the third trimester of pregnancy to some extent, and their combination can be used as an important index for the early prediction of FGR.
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Affiliation(s)
- Ying Zhang
- Department of Laboratory Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
| | - Teng Li
- Department of Interventional Radiology, The People’s Hospital of Weifang City, Weifang 261041, Shandong Province, China
| | - Chao-Yan Yue
- Department of Laboratory Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
| | - Yun Liu
- Department of Hematology, The People’s Hospital of Weifang City, Weifang 261041, Shandong Province, China
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Sayres L, Flockton AR, Ji S, Rey Diaz C, Gumina DL, Su EJ. Angiogenic Function of Human Placental Endothelial Cells in Severe Fetal Growth Restriction Is Not Rescued by Individual Extracellular Matrix Proteins. Cells 2023; 12:2339. [PMID: 37830553 PMCID: PMC10572031 DOI: 10.3390/cells12192339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/19/2023] [Accepted: 09/21/2023] [Indexed: 10/14/2023] Open
Abstract
Severe fetal growth restriction (FGR) is characterized by increased placental vascular resistance resulting from aberrant angiogenesis. Interactions between endothelial cells (ECs) and the extracellular matrix (ECM) are critical to the complex process of angiogenesis. We have previously found that placental stromal abnormalities contribute to impaired angiogenesis in severe FGR. The objective of this research is to better characterize the effect of individual ECM proteins on placental angiogenic properties in the setting of severe FGR. ECs were isolated from human placentae, either control or affected by severe FGR, and subjected to a series of experiments to interrogate the role of ECM proteins on adhesion, proliferation, migration, and apoptosis. We found impaired proliferation and migration of growth-restricted ECs. Although individual substrates did not substantially impact migratory capacity, collagens I, III, and IV partially mitigated proliferative defects seen in FGR ECs. Differences in adhesion and apoptosis between control and FGR ECs were not evident. Our findings demonstrate that placental angiogenic defects that characterize severe FGR cannot be explained by a singular ECM protein, but rather, the placental stroma as a whole. Further investigation of the effects of stromal composition, architecture, stiffness, growth factor sequestration, and capacity for remodeling is essential to better understand the role of ECM in impaired angiogenesis in severe FGR.
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Affiliation(s)
- Lauren Sayres
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado, CO 80045, USA
| | - Amanda R. Flockton
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado, CO 80045, USA
| | - Shuhan Ji
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado, CO 80045, USA
| | - Carla Rey Diaz
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado, CO 80045, USA
| | - Diane L. Gumina
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado, CO 80045, USA
| | - Emily J. Su
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado, CO 80045, USA
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado, CO 80045, USA
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Altered Cord Blood Lipid Concentrations Correlate with Birth Weight and Doppler Velocimetry of Fetal Vessels in Human Fetal Growth Restriction Pregnancies. Cells 2022; 11:cells11193110. [PMID: 36231072 PMCID: PMC9562243 DOI: 10.3390/cells11193110] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/26/2022] [Accepted: 09/26/2022] [Indexed: 11/17/2022] Open
Abstract
Fetal growth restriction (FGR) is associated with short- and long-term morbidity, often with fetal compromise in utero, evidenced by abnormal Doppler velocimetry of fetal vessels. Lipids are vital for growth and development, but metabolism in FGR pregnancy, where fetuses do not grow to full genetic potential, is poorly understood. We hypothesize that triglyceride concentrations are increased in placentas and that important complex lipids are reduced in cord plasma from pregnancies producing the smallest babies (birth weight < 5%) and correlate with ultrasound Dopplers. Dopplers (umbilical artery, UA; middle cerebral artery, MCA) were assessed longitudinally in pregnancies diagnosed with estimated fetal weight (EFW) < 10% at ≥29 weeks gestation. For a subset of enrolled women, placentas and cord blood were collected at delivery, fatty acids were extracted and targeted lipid class analysis (triglyceride, TG; phosphatidylcholine, PC; lysophosphatidylcholine, LPC; eicosanoid) performed by LCMS. For this sub-analysis, participants were categorized as FGR (Fenton birth weight, BW ≤ 5%) or SGA "controls" (Fenton BW > 5%). FGRs (n = 8) delivered 1 week earlier (p = 0.04), were 29% smaller (p = 0.002), and had 133% higher UA pulsatility index (PI, p = 0.02) than SGAs (n = 12). FGR plasma TG, free arachidonic acid (AA), and several eicosanoids were increased (p < 0.05); docosahexaenoic acid (DHA)-LPC was decreased (p < 0.01). Plasma TG correlated inversely with BW (p < 0.05). Plasma EET, non-esterified AA, and DHA correlated inversely with BW and directly with UA PI (p < 0.05). Placental DHA-PC and AA-PC correlated directly with MCA PI (p < 0.05). In fetuses initially referred for inadequate fetal growth (EFW < 10%), those with BW ≤ 5% demonstrated distinctly different cord plasma lipid profiles than those with BW > 5%, which correlated with Doppler PIs. This provides new insights into fetal lipidomic response to the FGR in utero environment. The impact of these changes on specific processes of growth and development (particularly fetal brain) have not been elucidated, but the relationship with Doppler PI may provide additional context for FGR surveillance, and a more targeted approach to nutritional management of these infants.
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De Asis-Cruz J, Andescavage N, Limperopoulos C. Adverse Prenatal Exposures and Fetal Brain Development: Insights From Advanced Fetal Magnetic Resonance Imaging. BIOLOGICAL PSYCHIATRY. COGNITIVE NEUROSCIENCE AND NEUROIMAGING 2022; 7:480-490. [PMID: 34848383 DOI: 10.1016/j.bpsc.2021.11.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/26/2021] [Accepted: 11/09/2021] [Indexed: 10/19/2022]
Abstract
Converging evidence from clinical and preclinical studies suggests that fetal vulnerability to adverse prenatal exposures increases the risk for neuropsychiatric diseases such as autism spectrum disorder, schizophrenia, and depression. Recent advances in fetal magnetic resonance imaging have allowed us to characterize typical fetal brain growth trajectories in vivo and to interrogate structural and functional alterations associated with intrauterine exposures, such as maternal stress, environmental toxins, drugs, and obesity. Here, we review proposed mechanisms for how prenatal influences disrupt neurodevelopment, including the role played by maternal and fetal inflammatory responses. We summarize insights from magnetic resonance imaging research in fetuses, highlight recent discoveries in normative fetal development using quantitative magnetic resonance imaging techniques (i.e., three-dimensional volumetry, proton magnetic resonance spectroscopy, placental diffusion imaging, and functional imaging), and discuss how baseline trajectories are shaped by prenatal exposures.
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Affiliation(s)
- Josepheen De Asis-Cruz
- Developing Brain Institute, Department of Radiology, Children's National Hospital, Washington, DC
| | - Nickie Andescavage
- Developing Brain Institute, Department of Radiology, Children's National Hospital, Washington, DC; Department of Neonatology, Children's National Hospital, Washington, DC
| | - Catherine Limperopoulos
- Developing Brain Institute, Department of Radiology, Children's National Hospital, Washington, DC.
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Wang YN, Ye Y, Zhou D, Guo ZW, Xiong Z, Gong XX, Jiang SW, Chen H. The Role of Syncytin in Placental Angiogenesis and Fetal Growth. Front Cell Dev Biol 2022; 10:852561. [PMID: 35493107 PMCID: PMC9039138 DOI: 10.3389/fcell.2022.852561] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/10/2022] [Indexed: 02/05/2023] Open
Abstract
Background: Syncytin, a retroviral envelope protein, is specifically expressed on trophoblast cells and mediates formation of the syncytiotrophoblast through fusogenic activity. Decreased expression of Syncytin was found in fetal growth restriction placentas. Results: By generating an inducible knockout of the syncytin-a gene in mice, we show a specific disruption of placental angiogenesis with abnormal formation of two syncytiotrophoblast layers. Consistent with the defects observed in vivo, conditioned medium collected from trophoblast cells, following Syncytin-1 knockdown, contains lower expression of vascular endothelial growth factor and placental growth factor, and higher levels of soluble fms-like protein kinase-1 in BeWo and HTR-8/SVneo cells which related with suppressed PI3K/Akt/mTOR pathway, and is reduced in ability to induce tube formation by HUVECs. Conclusion: Syncytin participates in angiogenesis during placental development was first identified both in vivo and in vitro. Here, we give a new sight on understanding syncytin and pathophysiology of placenta related disease such as fetal growth restriction.
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Affiliation(s)
- Ya-Nan Wang
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Yixin Ye
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
| | - Da Zhou
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
| | - Ze-Wen Guo
- Department of Obstetrics and Gynecology, Shantou Central Hospital, Shantou, China
| | - Zhelei Xiong
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
| | - Xing-Xing Gong
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
| | - Shi-Wen Jiang
- Center of Reproductive Medicine, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China
| | - Haibin Chen
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
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Porter B, Maulik D, Babbar S, Schrufer‐Poland T, Allsworth J, Ye SQ, Heruth DP, Lei T. Maternal plasma soluble neuropilin-1 is downregulated in fetal growth restriction complicated by abnormal umbilical artery Doppler: a pilot study. ULTRASOUND IN OBSTETRICS & GYNECOLOGY : THE OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY OF ULTRASOUND IN OBSTETRICS AND GYNECOLOGY 2021; 58:716-721. [PMID: 33533520 PMCID: PMC8597582 DOI: 10.1002/uog.23605] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 01/17/2021] [Accepted: 01/20/2021] [Indexed: 06/12/2023]
Abstract
OBJECTIVES Placental expression of neuropilin-1 (NRP1), a proangiogenic member of the vascular endothelial growth factor receptor family involved in sprouting angiogenesis, was recently discovered to be downregulated in pregnancies with fetal growth restriction (FGR) and abnormal umbilical artery (UA) Doppler. Soluble NRP1 (sNRP1) is an antagonist to NRP1; however, little is known about its role in normal and FGR pregnancies. This study tested the hypotheses that, first, sNRP1 would be detectable in maternal circulation and, second, its concentration would be upregulated in FGR pregnancies compared to those with normal fetal growth and this would correlate with the severity of the disease as assessed by UA Doppler. METHODS This was a prospective case-control pilot study of 40 singleton pregnancies (20 FGR cases and 20 uncomplicated controls) between 24 + 0 and 40 + 0 weeks' gestation followed in an academic perinatal center from January 2015 to May 2017. FGR was defined as an ultrasound-estimated fetal weight < 10th percentile for gestational age. The control group was matched to the FGR group for maternal age and gestational age at assessment. Fetal ultrasound biometry and UA Doppler were performed using standard protocols. Maternal plasma sNRP1 measurements were performed using a commercially available ELISA. RESULTS Contrary to the study hypothesis, maternal plasma sNRP1 levels were significantly decreased in FGR pregnancies as compared to those with normal fetal growth (137.4 ± 44.8 pg/mL vs 166.7 ± 36.9 pg/mL; P = 0.03). However, there was no significant difference in sNRP1 concentration between the control group and FGR pregnancies that had normal UA Doppler. Plasma sNRP1 was downregulated in FGR pregnancies with elevated UA systolic/diastolic ratio (P = 0.023) and those with UA absent or reversed end-diastolic flow (P = 0.005) in comparison to FGR pregnancies with normal UA Doppler. This suggests that biometrically small fetuses without hemodynamic compromise are small-for-gestational age rather than FGR. CONCLUSIONS This study demonstrated a significant decrease in maternal plasma sNRP1 concentration in growth-restricted pregnancies with fetoplacental circulatory compromise. These findings suggest a possible role of sNRP1 in modulating fetal growth and its potential as a biomarker for FGR. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
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Affiliation(s)
- B. Porter
- Department of Obstetrics and GynecologyUniversity of OklahomaOklahoma CityOKUSA
- Department of Obstetrics and GynecologyUniversity of Missouri Kansas CityKansas CityMOUSA
| | - D. Maulik
- Department of Obstetrics and GynecologyUniversity of Missouri Kansas CityKansas CityMOUSA
- Department of Biomedical and Health InformaticsUniversity of Missouri Kansas CityKansas CityMOUSA
| | - S. Babbar
- Department of Obstetrics and GynecologyUniversity of Missouri Kansas CityKansas CityMOUSA
| | - T. Schrufer‐Poland
- Department of Obstetrics and GynecologyUniversity of Missouri Kansas CityKansas CityMOUSA
- UCHealth Maternal Fetal Medicine ClinicColorado SpringsCOUSA
| | - J. Allsworth
- Department of Obstetrics and GynecologyUniversity of Missouri Kansas CityKansas CityMOUSA
- Department of Biomedical and Health InformaticsUniversity of Missouri Kansas CityKansas CityMOUSA
| | - S. Q. Ye
- Department of Biomedical and Health InformaticsUniversity of Missouri Kansas CityKansas CityMOUSA
| | - D. P. Heruth
- Department of Pediatrics, Children's Mercy HospitalUniversity of Missouri Kansas CityKansas CityMOUSA
| | - T. Lei
- Department of Biomedical and Health InformaticsUniversity of Missouri Kansas CityKansas CityMOUSA
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Vişan V, Balan RA, Costea CF, Cărăuleanu A, Haba RM, Haba MŞC, Socolov DG, Mogoş RA, Bogdănici CM, Nemescu D, Tănase DM, Turliuc MD, Cucu AI, Scripcariu DV, Toma BF, Popovici RM, Ciocoiu M, Petrariu FD. Morphological and histopathological changes in placentas of pregnancies with intrauterine growth restriction. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY 2021; 61:477-483. [PMID: 33544799 PMCID: PMC7864289 DOI: 10.47162/rjme.61.2.17] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Aim: The definition of fetal growth restriction (FGR) refers to the incapability of a fetus to achieve the appropriate estimated growth, with expected fetal weight below the 10th percentile calculated for its gestational age. Placental factors and hypoxemia are considered to be essential elements with influence on intrauterine growth restriction (IUGR) and fetal death. The purpose of the present study was to investigate the macroscopic and microscopic pathological findings regarding the placentas in pregnancies complicated by influence on IUGR. Patients, Materials and Methods: Our study included 42 third-trimester pregnant patients admitted to the Cuza Vodă Hospital of Obstetrics and Gynecology, Iaşi, Romania, in the last three years. Soon after delivery, the 42 placentas were collected and analyzed; 32 placentas came from cases previously diagnosed with influence on IUGR and were included in our study group. Ten other placentas included in the control group were selected from uncomplicated pregnancies. Standard Hematoxylin–Eosin (HE) staining method, as well as Periodic Acid–Schiff (PAS) staining, and immunohistochemical techniques for cluster of differentiation 31 (CD31) and collagen IV were used in order to highlight the morphological features of the studied placentas. Results: Our study revealed that reduced placental dimensions and eccentric umbilical cord insertion are correlated with the birthweight of the fetuses with IUGR (p<0.05). The most common histological finding in our study group was placental infarction later correlated with IUGR, but a certain causality could not be demonstrated, as this finding was also present in normal pregnancies. Other histopathological findings were also present in the influence on IUGR group, such as fibrin deposits, diffuse calcification, chronic villitis, avascular chronical villi, with no significant statistical correlations. CD31 was strongly immunoexpressed in the villous endothelial cells. Collagen IV presented a strong immunoreaction in the basement membrane and mesenchyme of the placental villi. Conclusions: Our study revealed a correlation between the dimensions of the diameters and volume of the maternal placenta and the presence of influence on IUGR. Moreover, it confirms the available data suggesting that the place of insertion of the umbilical cord is correlated with the weight of the fetus. Further studies with extended panel antibodies are needed in order to determine and complete the role of these morphological changes in the development of influence on IUGR.
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Affiliation(s)
- Valeria Vişan
- Department of Ophthalmology, Department of Morphofunctional Sciences I - Histology, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, Iaşi, Romania; ,
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10
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Araujo Júnior E, Zamarian AC, Caetano AC, Peixoto AB, Nardozza LM. Physiopathology of late-onset fetal growth restriction. Minerva Obstet Gynecol 2021; 73:392-408. [PMID: 33876907 DOI: 10.23736/s2724-606x.21.04771-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Fetal growth restriction (FGR) is defined as the inability of the fetus to reach its potential for genetic determination. FGR can have several causes, including genetic syndromes, chromosomal diseases, and infections; however, a vast majority of cases are probably attributed to impaired uterine and placental circulation. The relationships between abnormal placental development and FGR are complex, and studies are generally few, presenting confounding factors. Damage to the uteroplacental circulation associated with vasculogenesis and villus angiogenesis dysfunction are the main factors involved in subsequent FGR. The main receptors involved in FGR include hypoxia-inducible factor (HIF 1, 2, and 3), vascular endothelial growth factor (VEGF), placental growth factor (PlGF), vascular endothelial growth factor C (VEGF-C), soluble Flt-1, soluble endoglin (Seng), angiopoietin-1 and -2 (Ang-1 and Ang-2), tyrosine kinase receptor 1 (Flt-1), tyrosine kinase receptor 2 (Flt-2), vascular endothelial growth factor receptor (VEGFR) 1, 2 and 3, kinase domain receptor (KDR), and vascular endothelial growth factor receptor A (VEGFR-A). Furthermore, failure in trophoblastic invasion and remodeling of spiral arteries has been associated with FGR owing to poor placental perfusion. There are several possible causes for poor remodeling of spiral arteries, which probably vary on a case-to-case basis. Changes in the placental form, macroscopic and microscopic vascular lesions, inflammation, and genetic changes are also related to FGR. Based on gestational age at diagnosis, FGR can be classified as early- (˂32 weeks) and late-onset (≥32 weeks). Moreover, there exist several theories regarding possible pathophysiological differences between early- and late-onset FGR, with some postulating that it the same disease but at different stages or severity. Another hypothesis suggests that the change in the trophoblastic invasion of spiral arteries would be milder. In this article, we address the main mechanisms described in the pathophysiology of FGR and, later, the specific findings in late-onset FGR.
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Affiliation(s)
- Edward Araujo Júnior
- Paulista School of Medicine, Department of Obstetrics, Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil -
- Municipal University of São Caetano do Sul (USCS), São Paulo, Brazil -
| | - Ana C Zamarian
- Paulista School of Medicine, Department of Obstetrics, Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil
| | - Ana C Caetano
- Paulista School of Medicine, Department of Obstetrics, Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil
| | - Alberto B Peixoto
- Department of Obstetrics and Gynecology, Federal University of Triângulo Mineiro (UFTM), Uberaba, Brazil
- Mario Palmério University Hospital, University of Uberaba (UNIUBE), Uberaba, Brazil
| | - Luciano M Nardozza
- Paulista School of Medicine, Department of Obstetrics, Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil
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11
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Melamed N, Baschat A, Yinon Y, Athanasiadis A, Mecacci F, Figueras F, Berghella V, Nazareth A, Tahlak M, McIntyre HD, Da Silva Costa F, Kihara AB, Hadar E, McAuliffe F, Hanson M, Ma RC, Gooden R, Sheiner E, Kapur A, Divakar H, Ayres‐de‐Campos D, Hiersch L, Poon LC, Kingdom J, Romero R, Hod M. FIGO (international Federation of Gynecology and obstetrics) initiative on fetal growth: best practice advice for screening, diagnosis, and management of fetal growth restriction. Int J Gynaecol Obstet 2021; 152 Suppl 1:3-57. [PMID: 33740264 PMCID: PMC8252743 DOI: 10.1002/ijgo.13522] [Citation(s) in RCA: 246] [Impact Index Per Article: 61.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Fetal growth restriction (FGR) is defined as the failure of the fetus to meet its growth potential due to a pathological factor, most commonly placental dysfunction. Worldwide, FGR is a leading cause of stillbirth, neonatal mortality, and short- and long-term morbidity. Ongoing advances in clinical care, especially in definitions, diagnosis, and management of FGR, require efforts to effectively translate these changes to the wide range of obstetric care providers. This article highlights agreements based on current research in the diagnosis and management of FGR, and the areas that need more research to provide further clarification of recommendations. The purpose of this article is to provide a comprehensive summary of available evidence along with practical recommendations concerning the care of pregnancies at risk of or complicated by FGR, with the overall goal to decrease the risk of stillbirth and neonatal mortality and morbidity associated with this condition. To achieve these goals, FIGO (the International Federation of Gynecology and Obstetrics) brought together international experts to review and summarize current knowledge of FGR. This summary is directed at multiple stakeholders, including healthcare providers, healthcare delivery organizations and providers, FIGO member societies, and professional organizations. Recognizing the variation in the resources and expertise available for the management of FGR in different countries or regions, this article attempts to take into consideration the unique aspects of antenatal care in low-resource settings (labelled “LRS” in the recommendations). This was achieved by collaboration with authors and FIGO member societies from low-resource settings such as India, Sub-Saharan Africa, the Middle East, and Latin America.
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Affiliation(s)
- Nir Melamed
- Division of Maternal Fetal MedicineDepartment of Obstetrics and GynecologySunnybrook Health Sciences CentreUniversity of TorontoTorontoONCanada
| | - Ahmet Baschat
- Center for Fetal TherapyDepartment of Gynecology and ObstetricsJohns Hopkins UniversityBaltimoreMDUSA
| | - Yoav Yinon
- Fetal Medicine UnitDepartment of Obstetrics and GynecologySheba Medical CenterTel‐HashomerSackler Faculty of MedicineTel‐Aviv UniversityTel AvivIsrael
| | - Apostolos Athanasiadis
- Third Department of Obstetrics and GynecologyAristotle University of ThessalonikiThessalonikiGreece
| | - Federico Mecacci
- Maternal Fetal Medicine UnitDivision of Obstetrics and GynecologyDepartment of Biomedical, Experimental and Clinical SciencesUniversity of FlorenceFlorenceItaly
| | - Francesc Figueras
- Maternal‐Fetal Medicine DepartmentBarcelona Clinic HospitalUniversity of BarcelonaBarcelonaSpain
| | - Vincenzo Berghella
- Division of Maternal‐Fetal MedicineDepartment of Obstetrics and GynecologyThomas Jefferson UniversityPhiladelphiaPAUSA
| | - Amala Nazareth
- Jumeira Prime Healthcare GroupEmirates Medical AssociationDubaiUnited Arab Emirates
| | - Muna Tahlak
- Latifa Hospital for Women and ChildrenDubai Health AuthorityEmirates Medical AssociationMohammad Bin Rashid University for Medical Sciences, Dubai, United Arab Emirates
| | | | - Fabrício Da Silva Costa
- Department of Gynecology and ObstetricsRibeirão Preto Medical SchoolUniversity of São PauloRibeirão PretoSão PauloBrazil
| | - Anne B. Kihara
- African Federation of Obstetricians and GynaecologistsKhartoumSudan
| | - Eran Hadar
- Helen Schneider Hospital for WomenRabin Medical CenterPetach TikvaIsrael
- Sackler Faculty of MedicineTel‐Aviv UniversityTel AvivIsrael
| | - Fionnuala McAuliffe
- UCD Perinatal Research CentreSchool of MedicineNational Maternity HospitalUniversity College DublinDublinIreland
| | - Mark Hanson
- Institute of Developmental SciencesUniversity Hospital SouthamptonSouthamptonUK
- NIHR Southampton Biomedical Research CentreUniversity of SouthamptonSouthamptonUK
| | - Ronald C. Ma
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong Kong SARChina
- Hong Kong Institute of Diabetes and ObesityThe Chinese University of Hong KongHong Kong SARChina
| | - Rachel Gooden
- FIGO (International Federation of Gynecology and Obstetrics)LondonUK
| | - Eyal Sheiner
- Soroka University Medical CenterBen‐Gurion University of the NegevBe’er‐ShevaIsrael
| | - Anil Kapur
- World Diabetes FoundationBagsværdDenmark
| | | | | | - Liran Hiersch
- Sourasky Medical Center and Sackler Faculty of MedicineLis Maternity HospitalTel Aviv UniversityTel AvivIsrael
| | - Liona C. Poon
- Department of Obstetrics and GynecologyPrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong SAR, China
| | - John Kingdom
- Division of Maternal Fetal MedicineDepartment of Obstetrics and GynecologyMount Sinai HospitalUniversity of TorontoTorontoONCanada
| | - Roberto Romero
- Perinatology Research BranchEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthU.S. Department of Health and Human ServicesBethesdaMDUSA
| | - Moshe Hod
- Helen Schneider Hospital for WomenRabin Medical CenterPetach TikvaIsrael
- Sackler Faculty of MedicineTel‐Aviv UniversityTel AvivIsrael
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12
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Dai Y, Li TH, He X, Yan SB, Gao Y, Chen Y. The Effect and Mechanism of Asymmetric Dimethylarginine Regulating Trophoblastic Autophagy on Fetal Growth Restriction. Reprod Sci 2021; 28:2012-2022. [PMID: 33428125 DOI: 10.1007/s43032-020-00442-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 12/07/2020] [Indexed: 01/09/2023]
Abstract
Fetal growth restriction (FGR) is an important cause of perinatal death and adverse pregnancy outcomes. Asymmetric dimethylarginine (ADMA) is associated with FGR, but the mechanisms have not been thoroughly studied. Here, we determined the levels of ADMA and autophagy-related molecules in human blood samples and placental tissues. And we also used the human chorionic carcinoma cell line BeWo to investigate the mechanism of ADMA-induced FGR in vitro. Compared with the control group, ADMA levels in maternal blood and placenta were increased in patients with FGR, and the birth weight (BW) percentile was negatively correlated with maternal serum ADMA concentration in the FGR group. The expression of mammalian target of rapamycin (mTOR) in the placenta of the FGR group was lower than the control group, while the expression of Beclin-1 and microtubule-associated protein 1 light chain 3-II (LC3-II)/LC3-I was significantly increased in the FGR group. And the expression of matrix metalloproteinase 9 (MMP9) was decreased in the placenta of patients with FGR. In in vitro cell experiments, compared with the control group, the expression of mTOR and MMP9 in BeWo cells was decreased and the expression of Beclin-1 and LC3-II/LC3-I was increased in the ADMA-treated group. Moreover, ADMA had favorable effects on the formation of autophagic vacuoles, and the autophagy inhibitor 3-Methyladenine (3-MA) could reduce the autophagy-induction effect of ADMA on BeWo cells. This study found that ADMA could participate in the occurrence of FGR through inducing autophagy in trophoblasts.
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Affiliation(s)
- Yan Dai
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, 251# Yao Jia Yuan Road, Chao Yang District, Beijing, 100026, China
| | - Tian-He Li
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, 251# Yao Jia Yuan Road, Chao Yang District, Beijing, 100026, China
| | - Xin He
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, 251# Yao Jia Yuan Road, Chao Yang District, Beijing, 100026, China
| | - Song-Biao Yan
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, 251# Yao Jia Yuan Road, Chao Yang District, Beijing, 100026, China
| | - Yan Gao
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, 251# Yao Jia Yuan Road, Chao Yang District, Beijing, 100026, China.
| | - Yi Chen
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, 251# Yao Jia Yuan Road, Chao Yang District, Beijing, 100026, China.
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13
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Alfaidy N, Brouillet S, Rajaraman G, Kalionis B, Hoffmann P, Barjat T, Benharouga M, Murthi P. The Emerging Role of the Prokineticins and Homeobox Genes in the Vascularization of the Placenta: Physiological and Pathological Aspects. Front Physiol 2020; 11:591850. [PMID: 33281622 PMCID: PMC7689260 DOI: 10.3389/fphys.2020.591850] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/13/2020] [Indexed: 01/25/2023] Open
Abstract
Vasculogenesis and angiogenesis are key processes of placental development, which occur throughout pregnancy. Placental vasculogenesis occurs during the first trimester of pregnancy culminating in the formation of hemangioblasts from intra-villous stem cells. Placental angiogenesis occurs subsequently, forming new blood vessels from existing ones. Angiogenesis also takes place at the fetomaternal interface, allowing essential spiral arteriole remodeling to establish the fetomaternal circulation. Vasculogenesis and angiogenesis in animal models and in humans have been studied in a wide variety of in vitro, physiological and pathological conditions, with a focus on the pro- and anti-angiogenic factors that control these processes. Recent studies revealed roles for new families of proteins, including direct participants such as the prokineticin family, and regulators of these processes such as the homeobox genes. This review summarizes recent advances in understanding the molecular mechanisms of actions of these families of proteins. Over the past decade, evidence suggests increased production of placental anti-angiogenic factors, as well as angiogenic factors are associated with fetal growth restriction (FGR) and preeclampsia (PE): the most threatening pathologies of human pregnancy with systemic vascular dysfunction. This review also reports novel clinical strategies targeting members of these family of proteins to treat PE and its consequent effects on the maternal vascular system.
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Affiliation(s)
- Nadia Alfaidy
- Unité 1036, Institut National de la Santé et de la Recherche Médicale, Grenoble, France.,Department of Biology, University of Grenoble Alpes, Grenoble, France.,Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, Grenoble, France
| | - Sophie Brouillet
- INSERM U1203, Department of Reproductive Biology, University of Montpellier, Montpellier, France
| | - Gayathri Rajaraman
- Faculty of Health and Biomedicine, First Year College, Victoria University, St. Albans, VIC, Australia
| | - Bill Kalionis
- Department of Maternal-Fetal Medicine, Obstetrics and Gynaecology, Pregnancy Research Centre, Royal Women's Hospital, The University of Melbourne, Parkville, VIC, Australia
| | - Pascale Hoffmann
- Unité 1036, Institut National de la Santé et de la Recherche Médicale, Grenoble, France.,Department of Biology, University of Grenoble Alpes, Grenoble, France.,Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, Grenoble, France
| | - Tiphaine Barjat
- Unité 1059, Saint-Etienne Hospital, Institut National de la Santé et de la Recherche Médicale, Saint-Étienne, France
| | - Mohamed Benharouga
- Unité Mixte de Recherche 5249, Laboratoire de Chimie et Biologie des Métaux, Centre National de la Recherche Scientifique (CNRS), Grenoble, France
| | - Padma Murthi
- Department of Maternal-Fetal Medicine, Obstetrics and Gynaecology, Pregnancy Research Centre, Royal Women's Hospital, The University of Melbourne, Parkville, VIC, Australia.,Department of Pharmacology, The Ritchie Centre, Monash Biomedicine Discovery Institute, Hudson Institute of Medical Research, Monash University, Clayton, VIC, Australia
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14
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Eliesen GAM, van Hove H, Meijer MH, van den Broek PHH, Pertijs J, Roeleveld N, van Drongelen J, Russel FGM, Greupink R. Toxicity of anticancer drugs in human placental tissue explants and trophoblast cell lines. Arch Toxicol 2020; 95:557-571. [PMID: 33083868 PMCID: PMC7870638 DOI: 10.1007/s00204-020-02925-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 10/05/2020] [Indexed: 12/28/2022]
Abstract
The application of anticancer drugs during pregnancy is associated with placenta-related adverse pregnancy outcomes. Therefore, it is important to study placental toxicity of anticancer drugs. The aim of this study was to compare effects on viability and steroidogenesis in placental tissue explants and trophoblast cell lines. Third trimester placental tissue explants were exposed for 72 h (culture day 4–7) to a concentration range of doxorubicin, paclitaxel, cisplatin, carboplatin, crizotinib, gefitinib, imatinib, or sunitinib. JEG-3, undifferentiated BeWo, and syncytialised BeWo cells were exposed for 48 h to the same drugs and concentrations. After exposure, tissue and cell viability were assessed and progesterone and estrone levels were quantified in culture medium. Apart from paclitaxel, all compounds affected both cell and tissue viability at clinically relevant concentrations. Paclitaxel affected explant viability moderately, while it reduced cell viability by 50% or more in all cell lines, at 3–10 nM. Doxorubicin (1 µM) reduced viability in explants to 83 ± 7% of control values, whereas it fully inhibited viability in all cell types. Interference with steroid release in explants was difficult to study due to large variability in measurements, but syncytialised BeWo cells proved suitable for this purpose. We found that 1 µM sunitinib reduced progesterone release to 76 ± 6% of control values, without affecting cell viability. While we observed differences between the models for paclitaxel and doxorubicin, most anticancer drugs affected viability significantly in both placental explants and trophoblast cell lines. Taken together, the placenta should be recognized as a potential target organ for toxicity of anticancer drugs.
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Affiliation(s)
- Gaby A M Eliesen
- Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, (Route 137), PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
| | - Hedwig van Hove
- Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, (Route 137), PO Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Maartje H Meijer
- Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, (Route 137), PO Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Petra H H van den Broek
- Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, (Route 137), PO Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Jeanne Pertijs
- Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, (Route 137), PO Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Nel Roeleveld
- Department for Health Evidence, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
| | - Joris van Drongelen
- Department of Obstetrics and Gynecology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Frans G M Russel
- Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, (Route 137), PO Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Rick Greupink
- Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, (Route 137), PO Box 9101, 6500 HB, Nijmegen, The Netherlands
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15
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Chassen SS, Ferchaud-Roucher V, Palmer C, Li C, Jansson T, Nathanielsz PW, Powell TL. Placental fatty acid transport across late gestation in a baboon model of intrauterine growth restriction. J Physiol 2020; 598:2469-2489. [PMID: 32338384 PMCID: PMC7384518 DOI: 10.1113/jp279398] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 04/14/2020] [Indexed: 12/13/2022] Open
Abstract
KEY POINTS Intrauterine growth restriction (IUGR) is associated with perinatal morbidity and increased risk of lifelong disease, including neurodevelopmental impairment. Fatty acids (FA) are critical for normal brain development, although their transport across the placenta in IUGR pregnancies is poorly understood. The present study used a baboon model of IUGR (maternal nutrient restriction, MNR) to investigate placental expression of FA transport and binding proteins, and to determine gestational age-related changes in maternal and fetal plasma FA concentrations. We found MNR to be associated with increased placental expression of FA binding and transport proteins in late gestation, with fetal plasma FA concentrations that were similar to those of control animals. The present study is the first to report a profile of fetal and maternal plasma FA concentrations in a baboon model of growth restriction with data that suggest adaptation of placental transport to maintain delivery of critically needed FA. ABSTRACT Intrauterine growth restriction (IUGR) is associated with specific changes in placental transport of amino acids, folate and ions. However, little is known about placental fatty acid (FA) transport in IUGR. We hypothesized that placental FA transport proteins (FATP) and FA binding proteins (FABP) are up-regulated and fetal plasma FA concentrations are decreased at term in a baboon model of IUGR. Pregnant baboons were fed control or maternal nutrient restricted (MNR) diet (70% of control calories) from gestation day (GD) 30 (term 184 days). Plasma and placental samples were collected at GD120 (control n = 8, MNR n = 9), GD140 (control n = 6, MNR n = 7) and GD170 (control n = 6, MNR n = 6). Placentas were homogenized, and syncytiotrophoblast microvillous plasma membrane (MVM) and basal plasma membranes (BM) were isolated. Protein expression of FABP1, 3, 4 and 5 (homogenate) and FATP2, 4, and 6 (MVM, BM) was determined by Western blotting. FA content in maternal and umbilical vein plasma was measured by gas chromatography-mass spectrometry. Placental FABP1 and FABP5 expression was increased in MNR compared to controls at GD170, as was MVM FATP2 and FATP6 expression at GD140 and FATP2 expression at GD170. BM FATP4 and FATP6 expression was increased in MNR at GD140. Fetal plasma FA concentrations were similar in controls and MNR. These data suggest the adaptation of placental transport when aiming to maintain delivery of critically needed FAs for fetal growth and brain development.
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Affiliation(s)
- Stephanie S Chassen
- Department of Pediatrics, Section of Neonatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Veronique Ferchaud-Roucher
- University of Nantes, CHU Nantes, INRA, UMR 1280 Physiology of Nutritional Adaptations, Nantes, France
- Department of Obstetrics & Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Claire Palmer
- Department of Pediatrics, Section of Neonatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Cun Li
- Department of Animal Science, University of Wyoming, Laramie, WY, USA
- Southwest National Primate Research Center, San Antonio, TX, USA
| | - Thomas Jansson
- Department of Obstetrics & Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Peter W Nathanielsz
- Department of Animal Science, University of Wyoming, Laramie, WY, USA
- Southwest National Primate Research Center, San Antonio, TX, USA
| | - Theresa L Powell
- Department of Pediatrics, Section of Neonatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Obstetrics & Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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16
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Abid N, Embola J, Tryfonos Z, Bercher J, Ashton SV, Khalil A, Thilaganathan B, Cartwright JE, Whitley GS. Regulation of stanniocalcin-1 secretion by BeWo cells and first trimester human placental tissue from normal pregnancies and those at increased risk of developing preeclampsia. FASEB J 2020; 34:6086-6098. [PMID: 32162740 PMCID: PMC7318576 DOI: 10.1096/fj.201902426r] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 01/29/2020] [Accepted: 02/03/2020] [Indexed: 11/11/2022]
Abstract
Stanniocalcin-1 (STC-1) is a multi-functional glycosylated peptide present in the plasma of healthy women postpartum and increased further in pregnancies complicated by preeclampsia. Although the STC-1 gene is expressed by the placenta what regulates its secretion and from which cells at the feto-maternal interface is unknown. Here, we demonstrate for the first time that the syncytiotrophoblast and cytotrophoblast are a major site of STC-1 protein expression in first trimester placental tissue. Further, in response to low oxygen, first trimester chorionic villous tissue from pregnancies at increased risk of developing preeclampsia secreted significantly more STC-1 than normal tissue under the same conditions. Using the human trophoblast cell line BeWo we have shown that low oxygen increased the secretion of STC-1 but it required co-stimulation with the Adenosine-3', 5'-cyclic monophosphate (cAMP) analogue, 8-Bromo adenosine-3', 5'-cyclic monophosphate cAMP (8 Br-cAMP) to reach significance. Inhibition of Hypoxia inducible factor 2α (HIF-2α) and the Phosphatidylinositol-3 kinase (PI3 -Kinase)/AKT/Serum and glucocorticoid-induced kinase-1(SGK-1) pathway resulted in significant inhibition of STC-1 secretion. As both low oxygen and cAMP are known to play a central role in placental function, their regulation of STC-1 points to a potentially important role in the maintenance of a normal healthy pregnancy and we would hypothesize that it may act to protect against prolonged placental hypoxia seen in preeclampsia.
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Affiliation(s)
- Naila Abid
- Centre for Vascular Biology, Molecular and Clinical Sciences Research InstituteSt George'sUniversity of LondonLondonUK
| | - Joan Embola
- Centre for Vascular Biology, Molecular and Clinical Sciences Research InstituteSt George'sUniversity of LondonLondonUK
| | - Zoe Tryfonos
- Centre for Vascular Biology, Molecular and Clinical Sciences Research InstituteSt George'sUniversity of LondonLondonUK
| | - Julia Bercher
- Centre for Vascular Biology, Molecular and Clinical Sciences Research InstituteSt George'sUniversity of LondonLondonUK
| | - Sandra V. Ashton
- Centre for Vascular Biology, Molecular and Clinical Sciences Research InstituteSt George'sUniversity of LondonLondonUK
- Fetal Medicine UnitSt George's University Hospital NHS Foundation TrustLondonUK
| | - Asma Khalil
- Centre for Vascular Biology, Molecular and Clinical Sciences Research InstituteSt George'sUniversity of LondonLondonUK
- Fetal Medicine UnitSt George's University Hospital NHS Foundation TrustLondonUK
| | - Baskaran Thilaganathan
- Centre for Vascular Biology, Molecular and Clinical Sciences Research InstituteSt George'sUniversity of LondonLondonUK
- Fetal Medicine UnitSt George's University Hospital NHS Foundation TrustLondonUK
| | - Judith E. Cartwright
- Centre for Vascular Biology, Molecular and Clinical Sciences Research InstituteSt George'sUniversity of LondonLondonUK
| | - Guy S. Whitley
- Centre for Vascular Biology, Molecular and Clinical Sciences Research InstituteSt George'sUniversity of LondonLondonUK
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17
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Maged AM, Waly M, AbdelHak A, Eissa TS, Osman NK. Correlation of Doppler Velocimetry of Uterine and Umbilical Arteries with Placental Pathology in Pregnancy Associated with Intrauterine Growth Restriction. JOURNAL OF FETAL MEDICINE 2019. [DOI: 10.1007/s40556-019-00191-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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18
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Lv Y, Lv M, Ji X, Xue L, Rui C, Yin L, Ding H, Miao Z. Down-regulated expressed protein HMGB3 inhibits proliferation and migration, promotes apoptosis in the placentas of fetal growth restriction. Int J Biochem Cell Biol 2018; 107:69-76. [PMID: 30543931 DOI: 10.1016/j.biocel.2018.11.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 11/01/2018] [Accepted: 11/12/2018] [Indexed: 12/26/2022]
Abstract
Fetal growth restriction (FGR) is one of the major complications of pregnancy, which can lead to serious short-term and long-term diseases. High-mobility group box 3 (HMGB3) has been found to contribute to the development of many cancers. However, the role of HMGB3 in the pathogenesis of FGR is blank. Here, we measured the expression level of HMGB3 in the placenta tissues of six normal pregnancies and five FGR patients by western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). CCK8 assay, transwell assay and flow cytometry were used to detect the functional effects of overexpression and silencing of HMGB3 on the HTR8/SVneo trophoblast cell line. The results showed that the protein levels of HMGB3 were significantly decreased in FGR placentas compared to normal controls, while mRNA levels of HMGB3 were not significantly altered. Furthermore, when overexpressed of protein HMGB3 of the trophoblast cells, the proliferation and migration abilities were significantly promoted, and the apoptosis abilities of these cells were statistically inhibited. Cell functional experiments showed the opposite results when the expression of HMGB3 was silent. And the expression of cell function-related genes PCNA, Ki67, Tp53, Bax, MMP-2 and E-cadherin was observed to show corresponding changes by qRT-PCR. The results of mass spectrometry showed that HMGB3 may directly or indirectly interact with 71 proteins. In summary, our results indicated that HMGB3 might be of very great significance to the pathogenesis of FGR and might play the role by leading the dysfunction of placental villous trophoblast cells and through the interaction with some other proteins.
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Affiliation(s)
- Yan Lv
- Department of Obstetrics and Gynecology, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, 210004, China
| | - Mingming Lv
- Department of Breast, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, 210004, China; Nanjing Maternal and Child Health Institute, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, 210004, China
| | - Xiaohong Ji
- Department of Obstetrics and Gynecology, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, 210004, China
| | - Lu Xue
- Department of Obstetrics and Gynecology, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, 210004, China
| | - Can Rui
- Department of Obstetrics and Gynecology, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, 210004, China
| | - Lingfeng Yin
- Department of Obstetrics and Gynecology, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, 210004, China
| | - Hongjuan Ding
- Department of Obstetrics and Gynecology, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, 210004, China.
| | - Zhijing Miao
- Department of Obstetrics and Gynecology, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, 210004, China.
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19
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León RL, Li KT, Brown BP. A retrospective segmentation analysis of placental volume by magnetic resonance imaging from first trimester to term gestation. Pediatr Radiol 2018; 48:1936-1944. [PMID: 30027370 DOI: 10.1007/s00247-018-4213-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 06/08/2018] [Accepted: 07/12/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Abnormalities of the placenta affect 5-7% of pregnancies. Because disturbances in fetal growth are often preceded by dysfunction of the placenta or attenuation of its normal expansion, placental health warrants careful surveillance. There are limited normative data available for placental volume by MRI. OBJECTIVE To determine normative ranges of placental volume by MRI throughout gestation. MATERIALS AND METHODS In this cross-sectional retrospective analysis, we reviewed MRI examinations of pregnant females obtained between 2002 and 2017 at a single institution. We performed semi-automated segmentation of the placenta in images obtained in patients with no radiologic evidence of maternal or fetal pathology, using the Philips Intellispace Tumor Tracking Tool. RESULTS Placental segmentation was performed in 112 women and had a high degree of interrater reliability (single-measure intraclass correlation coefficient =0.978 with 95% confidence interval [CI] 0.956, 0.989; P<0.001). Normative data on placental volume by MRI increased nonlinearly from 6 weeks to 39 weeks of gestation, with wider variability of placental volume at higher gestational age (GA). We fit placental volumetric data to a polynomial curve of third order described as placental volume = -0.02*GA3 + 1.6*GA2 - 13.3*GA + 8.3. Placental volume showed positive correlation with estimated fetal weight (P=0.03) and birth weight (P=0.05). CONCLUSION This study provides normative placental volume by MRI from early first trimester to term gestation. Deviations in placental volume from normal might prove to be an imaging biomarker of adverse fetal health and neonatal outcome, and further studies are needed to more fully understand this metric. Assessment of placental volume should be considered in all routine fetal MRI examinations.
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Affiliation(s)
- Rachel L León
- Department of Pediatrics, Division of Neonatology, Riley Hospital for Children, Indiana University School of Medicine, 699 Riley Hospital Drive RR 208, Indianapolis, IN, 46202, USA.
| | - Kevin T Li
- Department of Radiology and Imaging Sciences, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Brandon P Brown
- Department of Radiology and Imaging Sciences, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA
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20
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Aviram A, Sherman C, Kingdom J, Zaltz A, Barrett J, Melamed N. Defining early vs late fetal growth restriction by placental pathology. Acta Obstet Gynecol Scand 2018; 98:365-373. [PMID: 30372519 DOI: 10.1111/aogs.13499] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 10/21/2018] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Although early and late fetal growth restriction have been suggested to be distinct entities, the optimal gestational age cut-off that differentiates the two conditions is currently unclear and has been arbitrarily set in previous studies between 32 and 37 weeks. We aimed to use placental pathology findings to determine that optimal gestational age cut-off between early and late fetal growth restriction. MATERIAL AND METHODS A retrospective cohort study of all women with singleton gestation who gave birth to a neonate diagnosed as small-for-gestational age (small-for-gestational age, defined as birthweight <10th percentile for gestational age) at a tertiary referral center between January 2001 and December 2015, and for whom placental pathology was available. Placental abnormalities were classified into lesions associated with maternal vascular malperfusion (MVM), fetal vascular malperfusion, placental hemorrhage and chronic villitis. Placental findings were analyzed as a function of gestational age at birth. The analysis was repeated in the subgroups of women without hypertensive complications of pregnancy (to reflect changes associated with isolated small-for-gestational age) and of neonates with severe small-for-gestational age (defined as birthweight <5th percentile), which are more likely to represent true fetal growth restriction. RESULTS A total of 895 women met the inclusion criteria. The only histological finding that changed with gestational age was MVM pathology, which decreased in frequency with increasing gestational age. We identified a considerable drop in the rate of MVM lesions at 33 weeks of gestation. The rate of MVM pathology in placentas of infants born before 330/7 weeks was significantly higher than that observed in placentas of infants born at 330/7 weeks or longer: 71.6% vs 27.4%, P < 0.001 for ≥2 MVM lesions, and 35.5% vs 3.5%, P < 0.001 for ≥3 MVM lesions. These findings persisted in the subgroups of women without hypertensive complications of pregnancy (n = 662) and of neonates with severe small-for-gestational age (n = 464). CONCLUSIONS Using placental pathology as a direct measure of the mechanisms underlying fetal growth restriction, the optimal gestational age at birth cut-off which differentiates early from late fetal growth restriction appears to be 330/7 weeks.
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Affiliation(s)
- Amir Aviram
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Sunnybrook Health Sciences Center, University of Toronto, Toronto, Ontario, Canada.,The Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Christopher Sherman
- Division of Anatomic Pathology, Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Center , University of Toronto, Toronto, Ontario, Canada
| | - John Kingdom
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Arthur Zaltz
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Sunnybrook Health Sciences Center, University of Toronto, Toronto, Ontario, Canada
| | - Jon Barrett
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Sunnybrook Health Sciences Center, University of Toronto, Toronto, Ontario, Canada
| | - Nir Melamed
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Sunnybrook Health Sciences Center, University of Toronto, Toronto, Ontario, Canada
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21
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Kwiatkowski S, Bednarek-Jędrzejek M, Ksel J, Tousty P, Kwiatkowska E, Cymbaluk A, Rzepka R, Chudecka-Głaz A, Dołęgowska B, Torbè A. sFlt-1/PlGF and Doppler ultrasound parameters in SGA pregnancies with confirmed neonatal birth weight below 10th percentile. Pregnancy Hypertens 2018; 14:79-85. [PMID: 30527123 DOI: 10.1016/j.preghy.2018.08.448] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 08/02/2018] [Accepted: 08/15/2018] [Indexed: 11/30/2022]
Abstract
We explored whether there was a relationship between the sFlt-1/PlGF ratio in early-late and late-onset SGA patients and whether it is associated with neonatal birth weight. MATERIAL/METHODS 110 patients who were diagnosed with a fetal weight below the 10th percentile for gestational age and who at the same time delivered neonates with a birth weight below the 10th percentile for gestational age. For each of the patients sFlt-1, PlGF and the sFlt-1/PlGF ratio were studied and uterine artery (UtA) and umbilical artery (UA) Doppler were performed. RESULTS sFlt-1/PlGF ratios and neonatal birth weight which showed significant negative correlation across the entire population studied (R = -0.46, p < 0.001). In late-onset SGA patients this negative correlation was observed, as well (R = -0.54, p < 0.001) In the group of patients with pregnancies older than 34 weeks and an sFlt-1/PlGF ratio ≥38, we observed a significantly lower neonatal birth weight when compared to the same gestational age group with an sFlt-1/PlGF ratio <38 (2045 g vs 2405 g, p < 0.001). CONCLUSION Late-onset SGA syndromes are characterized by lower sFlt-1/PlGF ratios, which indicates a lower degree of placental function impairment. The sFlt-1/PlGF ratio can be a predictor of more significant growth disorders and a lower neonatal birth weight. The sFlt-1/PlGF ratio can be helpful in distinguishing between disordered angiogenesis-dependent and other causes of late-onset SGA cases.
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Affiliation(s)
- Sebastian Kwiatkowski
- Department of Obstetrics and Gynecology, Pomeranian Medical University, Szczecin, Poland.
| | | | - Joanna Ksel
- Department of Obstetrics and Gynecology, Pomeranian Medical University, Szczecin, Poland
| | - Piotr Tousty
- Department of Obstetrics and Gynecology, Pomeranian Medical University, Szczecin, Poland
| | - Ewa Kwiatkowska
- Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, Szczecin, Poland
| | - Aneta Cymbaluk
- Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland
| | - Rafał Rzepka
- Department of Obstetrics and Gynecology, Pomeranian Medical University, Szczecin, Poland
| | - Anita Chudecka-Głaz
- Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland
| | - Barbara Dołęgowska
- Department of Microbiology, Immunology and Laboratory Medicine, Pomeranian Medical University, Szczecin, Poland
| | - Andrzej Torbè
- Department of Obstetrics and Gynecology, Pomeranian Medical University, Szczecin, Poland
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22
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Ultrasound Elastography can Detect Placental Tissue Abnormalities. Radiol Oncol 2018; 52:129-135. [PMID: 30018515 PMCID: PMC6043885 DOI: 10.2478/raon-2018-0024] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 04/23/2018] [Indexed: 12/21/2022] Open
Abstract
Background In this prospective cohort study, we examined the utility of elastography to evaluate the fetus and placenta. Patients and methods Pregnant women in their third trimester of pregnancy, by which time the placenta has formed, were included in this study. A total of 111 women underwent ultrasound examinations, including elastography. Elastographic evaluation was performed using two protocols. First, the placental index (PI) was measured, which quantitatively assesses the hardness of tissue. Second, regions of interest (ROI) were categorized into 3-step scores according to the frequency of the blue area (hardness of placental tissue score [HT score]), which is a qualitative method. After delivery, 40 of the 111 placentas were pathologically examined. Results The average PI was 44.3 (± 29.4) in the in utero SGA group, which was significantly higher than that in the normal group (8.8 (± 10.0); p < 0.01) during pregnancy. There was a significant correlation between the PI and z score for estimated fetal weight (EFW) (r = -0.55; p < 0.01). Moreover, a significant positive correlation was observed between the PI and the z score of birth weight (r = -0.39; p < 0.01). Pathological ischemia findings of the placenta were identified in 67% of the HT score 3 group, representing 6 of the 9 patients, and in 20% of the HT score 1 group, representing only 3 of the 15 patients. Conclusions Placental hardness, as determined by elastography, correlates with both lower estimated fetal body weight and birth weight. These results suggest that ultrasound elastography in the placenta may be an additional marker of intrauterine fetal well-being.
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Szpera-Gozdziewicz A, Kosicka K, Gozdziewicz T, Krzyscin M, Wirstlein P, Siemiatkowska A, Glowka F, Wender-Ozegowska E, Breborowicz GH. Maternal Serum Endocan Concentration in Pregnancies Complicated by Intrauterine Growth Restriction. Reprod Sci 2018; 26:370-376. [PMID: 29742984 DOI: 10.1177/1933719118773480] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVES Endocan plays a role in the development of vascular tissue in health and disease and is an indicator of endothelial cells activation and angiogenesis. Therefore, this study aimed to investigate the relationship between maternal endocan serum level and intrauterine growth restriction (IUGR) as well as ultrasound Doppler flow measurements indicating placental insufficiency. METHODS This study included a group of women with IUGR (n = 37) and a group of healthy pregnant women (controls, n = 37). The endocan serum concentrations were assessed using commercially available enzyme-linked immunosorbent assay kit. Every woman underwent an ultrasound examination with Doppler flow measurements of the uterine arteries, umbilical vessels, and fetal middle cerebral artery. We used the cerebroplacental ratio (CPR) to determine placental insufficiency. RESULTS We found significant differences in median (interquartile) endocan serum level (pg/mL) between study and control groups (464 [374-532] vs 339 [189-496], respectively; P < .001). The endocan serum level correlated neither with umbilical cord blood gases nor with Apgar score. Ultrasound Doppler findings revealed significant differences in middle cerebral artery pulsatility index (PI), umbilical artery PI, CPR, as well as mean uterine arteries PI between IUGR group and controls. In the study group, we found significant correlations between the serum endocan and CPR ( R = 0.56, P < .001) as well as between serum endocan and mean uterine arteries PI ( R = 0.46, P = .006). CONCLUSION Endocan is likely involved in the pathogenesis of IUGR in pregnant women and possibly is a useful marker of endothelial dysfunction in these cases.
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Affiliation(s)
- Agata Szpera-Gozdziewicz
- 1 Department of Perinatology and Gynecology, Poznan University of Medical Sciences, Poznan, Poland
| | - Katarzyna Kosicka
- 2 Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznan, Poland
| | - Tomasz Gozdziewicz
- 3 Division of Gynecology, Department of Perinatology and Gynecology, Poznan University of Medical Sciences, Poznan, Poland
| | - Mariola Krzyscin
- 1 Department of Perinatology and Gynecology, Poznan University of Medical Sciences, Poznan, Poland
| | - Przemyslaw Wirstlein
- 4 Division of Reproduction, Department of Obstetrics, Gynecology and Gynecologic Oncology, Poznan University of Medical Sciences, Poznan, Poland
| | - Anna Siemiatkowska
- 2 Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznan, Poland
| | - Franciszek Glowka
- 2 Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznan, Poland
| | - Ewa Wender-Ozegowska
- 2 Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznan, Poland
| | - Grzegorz H Breborowicz
- 1 Department of Perinatology and Gynecology, Poznan University of Medical Sciences, Poznan, Poland
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24
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Verheecke M, Cortès Calabuig A, Finalet Ferreiro J, Brys V, Van Bree R, Verbist G, Everaert T, Leemans L, Gziri MM, Boere I, Halaska MJ, Vanhoudt J, Amant F, Van Calsteren K. Genetic and microscopic assessment of the human chemotherapy-exposed placenta reveals possible pathways contributive to fetal growth restriction. Placenta 2018; 64:61-70. [PMID: 29626982 DOI: 10.1016/j.placenta.2018.03.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Revised: 03/06/2018] [Accepted: 03/07/2018] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Fetal growth restriction (FGR) carries an increased risk of perinatal mortality and morbidity. A major cause of FGR is placental insufficiency. After in utero chemotherapy-exposure, an increased incidence of FGR has been reported. In a prospective cohort study we aimed to explore which pathways may contribute to chemotherapy-associated FGR. METHODS Placental biopsies were collected from 25 cancer patients treated with chemotherapy during pregnancy, and from 66 control patients. Differentially expressed pathways between chemotherapy-exposed patients and controls were examined by whole transcriptome shotgun sequencing (WTSS) and Ingenuity Pathway Analysis (IPA). Immunohistochemical studies for 8-OHdG and eNOS (oxidative DNA damage), proliferation (PCNA) and apoptosis (Cleaved Caspase 3) were performed. The expression level of eNOS, PCNA and IGFBP6 was verified by real-time quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR). RESULTS Most differential expressed genes between chemotherapy-exposed patients and controls were related to growth, developmental processes, and radical scavenging networks. The duration of chemotherapy exposure had an additional impact on the expression of genes related to the superoxide radicals degeneration network. Immunohistochemical analyses showed a significantly increased expression of 8-OHdG (P = 0.003) and a decreased expression of eNOS (P=0.015) in the syncytiotrophoblast of the placenta of cancer patients. A decreased expression of PCNA was detected by immunohistochemistry as RT-qPCR (NS). CONCLUSION Chemotherapy exposure during pregnancy results in an increase of oxidative DNA damage and might impact the placental cellular growth and development, resulting in an increased incidence of FGR in this specific population. Further large prospective cohort studies and longitudinal statistical analyses are needed.
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Affiliation(s)
- M Verheecke
- Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Department of Obstetrics and Gynecology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | | | | | - V Brys
- Genomics Core, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - R Van Bree
- Department of Reproduction and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - G Verbist
- Genomics Core, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - T Everaert
- Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - L Leemans
- Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - M M Gziri
- Department of Obstetrics and Gynecology, Cliniques Universitaires St. Luc, Hippokrateslaan 10, 1200 Brussels, Belgium
| | - I Boere
- Department of Medical Oncology, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
| | - M J Halaska
- Department of Obstetrics and Gynaecology, 3rd Medical Faculty, Charles University, Prague 5, Faculty Hospital Kralovske Vinohrady, Srobarova 1150/50, 100 34, Prague 10, Czech Republic
| | - J Vanhoudt
- Genomics Core, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - F Amant
- Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Department of Gynaecologic Oncology, Center for Gynaecologic Oncology, Amsterdam, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
| | - K Van Calsteren
- Department of Obstetrics and Gynecology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium; Department of Reproduction and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
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25
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Verheecke M, Hermans E, Tuyaerts S, Souche E, Van Bree R, Verbist G, Everaert T, Cortès-Calabuig A, Van Houdt J, Van Calsteren K, Amant F. Acute Drug Effects on the Human Placental Tissue: The Development of a Placental Murine Xenograft Model. Reprod Sci 2018; 25:1637-1648. [PMID: 29439620 DOI: 10.1177/1933719118756771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE A pilot study was conducted to establish a human placental xenograft, which could serve as a model to evaluate the effect of toxic exposures during pregnancy. STUDY DESIGN The protocol consisted of engraftment of third-trimester human placental tissue in immunocompromised mice, after induction of a pseudo-pregnancy state by ovariectomy and progesterone supplementation. To validate the model, the placental tissue before and after engraftment was examined by immunohistochemistry, fluorescence-activated cell sorting (FACS), single-nucleotide polymorphism (SNP) genotyping, and whole transcriptome sequencing (WTSS). The human chorion gonadotropin (hCG) production in serum and urine was examined by enzyme-linked immunosorbent assay. RESULTS Microscopic evaluation of the placental tissue before and after engraftment revealed a stable morphology and preserved histological structure of the human tissue. Viable trophoblast was present after engraftment and remained stable over time. Vascularization and hormonal secretion (hCG) were present till 3 weeks after engraftment. Thirty-one SNPs were equally present, and there was a stable expression level for 56 451 genes evaluated by whole transcriptome sequencing. CONCLUSION Although this human placental xenograft model cannot copy the unique uterine environment in which the placenta develops and interacts between the mother and the fetus, it could be a suitable tool to evaluate the acute impact and adaptive processes of the placental tissue to environmental changes.
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Affiliation(s)
- Magali Verheecke
- 1 Department of Oncology, KU Leuven, Leuven, Belgium.,2 Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium
| | - Els Hermans
- 3 TRACE (the patient-derived human xenograft platform), Catholic University of Leuven, KU Leuven, Leuven, Belgium.,4 Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.,5 Genomics Core, KU Leuven, Leuven, Belgium
| | | | - Erika Souche
- 4 Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.,5 Genomics Core, KU Leuven, Leuven, Belgium
| | - Rita Van Bree
- 6 Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Godelieve Verbist
- 6 Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Tina Everaert
- 1 Department of Oncology, KU Leuven, Leuven, Belgium
| | - Alvaro Cortès-Calabuig
- 4 Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.,5 Genomics Core, KU Leuven, Leuven, Belgium
| | - Jeroen Van Houdt
- 4 Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.,5 Genomics Core, KU Leuven, Leuven, Belgium
| | - Kristel Van Calsteren
- 2 Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium.,6 Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Frederic Amant
- 1 Department of Oncology, KU Leuven, Leuven, Belgium.,7 Center for Gynecologic Oncology Amsterdam (CGOA), Netherlands Cancer Institute, (NKI), Amsterdam, the Netherlands
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The correlation of morphological and thrombotic villous arterial lesions with fetal Doppler echocardiographic measurements in the placentas of low-risk term pregnancies. Eur J Obstet Gynecol Reprod Biol 2018; 223:39-45. [PMID: 29475119 DOI: 10.1016/j.ejogrb.2018.02.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 01/25/2018] [Accepted: 02/08/2018] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Few studies have correlated the placental vasculature with fetal cardiac function other than umbilical artery Doppler assessment in low-risk pregnancies. We assessed the contribution of the placental vasculature to fetal echocardiographic parameters using histopathological and morphometric analyses of placental resistance arteries. STUDY DESIGN Thirty-four low-risk singleton term pregnancies were assessed, including 24 thrombosis-negative cases (no/minimal gross and histological placental abnormalities) and 10 thrombosis-positive cases (histologically identified chorionic plate/stem vessel thrombosis). Fetal ventricular Doppler inflow velocities (E and A waves) and myocardial systolic (S'), early (E'), and late diastolic (A') tissue Doppler velocities were measured within three days before birth. The myocardial performance index (MPI') was calculated. Morphometric variables of placental stem villi arterioles (external diameter 10-150 μm) were examined, including the mean arteriolar density, total cross-sectional lumen area, and wall area/total vessel area (WA/TVA) ratio. RESULTS The thrombosis-positive group had a higher umbilical artery pulsatility index and a lower tricuspid E'/A' ratio compared to the thrombosis-negative group. The WA/TVA ratio of stem villi arterioles was negatively correlated with tricuspid E, A, and S' velocities as well as the E/E' ratio (n = 34). The tricuspid MPI' was positively correlated with the total cross-sectional lumen area of stem villi arterioles (n = 34). CONCLUSION We conclude that changes in several fetal echocardiographic parameters are associated with placental vascular histopathological and morphological characteristics in a low-risk population. Further studies are needed to assess whether fetal echocardiographic assessment is a promising prenatal predictor of placental vascular histopathological and morphological characteristics in the general population.
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Vandenbroucke T, Verheecke M, Fumagalli M, Lok C, Amant F. Effects of cancer treatment during pregnancy on fetal and child development. THE LANCET CHILD & ADOLESCENT HEALTH 2017; 1:302-310. [PMID: 30169185 DOI: 10.1016/s2352-4642(17)30091-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 08/07/2017] [Accepted: 08/08/2017] [Indexed: 01/08/2023]
Abstract
It has become clear that, for specific cancers and under well defined circumstances, oncological treatment in pregnancy is possible. In this Review, we summarise the evidence on fetal, neonatal, short-term, and long-term effects of prenatal exposure to cancer treatment on the child. So far, outcomes of children are generally reassuring, but long-term follow-up is insufficient. The most important risks of chemotherapy during pregnancy are preterm birth and babies being small for gestational age. Chemotherapy in the first trimester is contraindicated because of an increased risk of congenital malformations. Studies on outcomes of children exposed to radiotherapy, targeted therapy, or hormonal therapy in pregnancy are scarce. Careful registration of women undergoing cancer treatment in pregnancy and long-term follow-up of their children are important. Comprehensive documentation of the mental and physical status of children exposed to cancer treatment in utero will allow physicians and parents to best decide whether to treat cancer during pregnancy.
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Affiliation(s)
- Tineke Vandenbroucke
- Department of Oncology, KU Leuven-University of Leuven, Leuven, Belgium; Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium
| | - Magali Verheecke
- Department of Oncology, KU Leuven-University of Leuven, Leuven, Belgium; Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium
| | - Monica Fumagalli
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy; Università degli Studi di Milano, Milan, Italy
| | - Christianne Lok
- Center Gynecologic Oncology, Antoni van Leeuwenhoek Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Frédéric Amant
- Department of Oncology, KU Leuven-University of Leuven, Leuven, Belgium; Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium; Center Gynecologic Oncology, Antoni van Leeuwenhoek Netherlands Cancer Institute, Amsterdam, Netherlands; Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
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The influence of prenatal exercise and pre-eclampsia on maternal vascular function. Clin Sci (Lond) 2017; 131:2223-2240. [PMID: 28798074 DOI: 10.1042/cs20171036] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 07/03/2017] [Accepted: 07/06/2017] [Indexed: 01/10/2023]
Abstract
During healthy pregnancy, the cardiovascular system undergoes diverse adaptations to support adequate transfer of oxygen and nutrients from mother to fetus. In order to accommodate the large expansion of blood volume and associated cardiac output, the structure, mechanics, and function of the arteries are altered. Specifically, in healthy pregnancy there is a remodeling of arteries (increased angiogenesis and vasodilation), a generalized reduction in arterial stiffness (increased compliance), and an enhanced endothelial function. The development of pregnancy complications, specifically pre-eclampsia, is associated with poor placentation (decreased angiogenesis), increased arterial stiffness, and vascular dysfunction (reduced endothelial function). Many of the positive adaptations that occur in healthy pregnancy are enhanced in response to chronic exercise. Specifically, placental angiogenesis and endothelial function have been shown to improve to a greater extent in women who are active during their pregnancy compared with those who are not. Prenatal exercise may be important in helping to reduce the risk of vascular dysfunction in pregnancy. However, our knowledge of the vascular adaptations resulting from maternal exercise is limited. This review highlights maternal vascular adaptations occurring during healthy pregnancy, and contrasts the vascular maladaptation associated with pre-eclampsia. Finally, we discuss the role of prenatal exercise on vascular function in the potential prevention of vascular complications associated with pre-eclampsia.
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Xu H, Pausch H, Venhoranta H, Rutkowska K, Wurmser C, Rieblinger B, Flisikowska T, Frishman D, Zwierzchowski L, Fries R, Andersson M, Kind A, Schnieke A, Flisikowski K. Maternal placenta modulates a deleterious fetal mutation†. Biol Reprod 2017; 97:249-257. [DOI: 10.1093/biolre/iox064] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 06/23/2017] [Indexed: 12/13/2022] Open
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p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction. Cell Death Dis 2017; 8:e2730. [PMID: 28383551 PMCID: PMC5477575 DOI: 10.1038/cddis.2017.127] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 02/03/2017] [Accepted: 02/08/2017] [Indexed: 01/21/2023]
Abstract
Placental insufficiency jeopardizes prenatal development, potentially leading to intrauterine growth restriction (IUGR) and stillbirth. Surviving fetuses are at an increased risk for chronic diseases later in life. IUGR is closely linked with altered trophoblast and placental differentiation. However, due to a paucity of mechanistic insights, suitable biomarkers and specific therapies for IUGR are lacking. The transcription factor p45 NF-E2 (nuclear factor erythroid derived 2) has been recently found to regulate trophoblast differentiation in mice. The absence of p45 NF-E2 in trophoblast cells causes IUGR and placental insufficiency in mice, but mechanistic insights are incomplete and the relevance of p45 NF-E2 for human syncytiotrophoblast differentiation remains unknown. Here we show that p45 NF-E2 negatively regulates human syncytiotrophoblast differentiation and is associated with IUGR in humans. Expression of p45 NF-E2 is reduced in human placentae complicated with IUGR compared with healthy controls. Reduced p45 NF-E2 expression is associated with increased syncytiotrophoblast differentiation, enhanced glial cells missing-1 (GCM1) acetylation and GCM1 desumoylation in IUGR placentae. Induction of syncytiotrophoblast differentiation in BeWo and primary villous trophoblast cells with 8-bromo-adenosine 3',5'-cyclic monophosphate (8-Br-cAMP) reduces p45 NF-E2 expression. Of note, p45 NF-E2 knockdown is sufficient to increase syncytiotrophoblast differentiation and GCM1 expression. Loss of p45 NF-E2 using either approach resulted in CBP-mediated GCM1 acetylation and SENP-mediated GCM1 desumoylation, demonstrating that p45 NF-E2 regulates post-translational modifications of GCM1. Functionally, reduced p45 NF-E2 expression is associated with increased cell death and caspase-3 activation in vitro and in placental tissues samples. Overexpression of p45 NF-E2 is sufficient to repress GCM1 expression, acetylation and desumoylation, even in 8-Br-cAMP exposed BeWo cells. These results suggest that p45 NF-E2 negatively regulates differentiation and apoptosis activation of human syncytiotrophoblast by modulating GCM1 acetylation and sumoylation. These studies identify a new pathomechanism related to IUGR in humans and thus provide new impetus for future studies aiming to identify new biomarkers and/or therapies of IUGR.
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Dall’Asta A, Brunelli V, Prefumo F, Frusca T, Lees CC. Early onset fetal growth restriction. Matern Health Neonatol Perinatol 2017; 3:2. [PMID: 28116113 PMCID: PMC5241928 DOI: 10.1186/s40748-016-0041-x] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 12/27/2016] [Indexed: 01/01/2023] Open
Abstract
Fetal growth restriction (FGR) diagnosed before 32 weeks is identified by fetal smallness associated with Doppler abnormalities and is associated with significant perinatal morbidity and mortality and maternal complications. Recent studies have provided new insights into pathophysiology, management options and postnatal outcomes of FGR. In this paper we review the available evidence regarding diagnosis, management and prognosis of fetuses diagnosed with FGR before 32 weeks of gestation.
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Affiliation(s)
- Andrea Dall’Asta
- Centre for Fetal Care, Queen Charlotte’s and Chelsea Hospital, Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS United Kingdom
- Department of Obstetrics & Gynecology, University of Parma, Parma, Italy
| | - Valentina Brunelli
- Department of Obstetrics and Gynaecology, Maternal-Fetal Medicine Unit, University of Brescia, Brescia, Italy
| | - Federico Prefumo
- Department of Obstetrics and Gynaecology, Maternal-Fetal Medicine Unit, University of Brescia, Brescia, Italy
| | - Tiziana Frusca
- Department of Obstetrics & Gynecology, University of Parma, Parma, Italy
| | - Christoph C Lees
- Centre for Fetal Care, Queen Charlotte’s and Chelsea Hospital, Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS United Kingdom
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
- Department of Development and Regeneration, KU Leuven, Belgium
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Maulik D, De A, Ragolia L, Evans J, Grigoryev D, Lankachandra K, Mundy D, Muscat J, Gerkovich MM, Ye SQ. Down-regulation of placental neuropilin-1 in fetal growth restriction. Am J Obstet Gynecol 2016; 214:279.e1-279.e9. [PMID: 26409917 DOI: 10.1016/j.ajog.2015.09.068] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Revised: 09/03/2015] [Accepted: 09/14/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Fetal growth restriction (FGR) is associated with adverse outcomes extending from fetal to adult life, and thus, constitutes a major health care challenge. Fetuses with progressive growth restriction show increasing impedance in the umbilical artery flow, which may become absent during end-diastole. Absent end-diastolic flow (AEDF) is associated with adverse perinatal outcomes including stillbirths and perinatal asphyxia. Placentas from such pregnancies demonstrate deficient fetoplacental vascular branching. Current evidence, moreover, indicates an antiangiogenic state in maternal circulation in several pregnancy complications including preeclampsia, small-for-gestational-age births, fetal death, and preterm labor. The angiogenic mediators in maternal circulation are predominantly of placental origin. Information, however, on the role of specific proangiogenic and antiangiogenic mechanisms operating at the placental level remains limited. Elucidation of these placenta-specific angiogenic mechanisms will not only extend our understanding of the causal pathway for restricted fetal growth but may also lead to the development of biomarkers that may allow early recognition of FGR. OBJECTIVE We sought to test the hypothesis that fetoplacental angiogenic gene expression is altered in pregnancies complicated with FGR and umbilical artery Doppler AEDF. STUDY DESIGN Placental samples were collected from FGR pregnancies complicated with umbilical artery Doppler AEDF (study group, n = 7), and from uncomplicated pregnancies (control group, n = 7), all delivered by cesarean during the last trimester of pregnancy. Angiogenic oligonucleotide microarray analysis was performed and was corroborated by quantitative real-time polymerase chain reaction, Western blot analysis, and immunohistochemistry. The Student t test with Bonferroni correction was used with P < .05 considered statistically significant. Independent groups t test was used to analyze the immunostain intensity scores with a P < .05 considered statistically significant. RESULTS Our microarray results showed that among several differentially expressed angiogenic genes in the growth-restricted group, only the down-regulation of neuropilin (NRP)-1 was most significant (P < .0007). Quantitative real-time polymerase chain reaction confirmed a significantly lower NRP-1 gene expression in the FGR group than in the control group (mean ± SD (ˆ)cycle threshold: 0.624 ± 0.55 and 1.325 ± 0.84, respectively, P = .04). Western blot validated significantly lower NRP-1 protein expression in the FGR group than in the control group (mean ± SD NRP-1/β-actin ratio: 0.13 ± 0.04 and 0.34 ± 0.05, respectively, P < .001). Finally, immunohistochemistry of placental villi further corroborated a significantly decreased expression of NRP-1 in the FGR group (P = .006). CONCLUSION The study demonstrated significant down-regulation of placental NRP-1 expression in FGR pregnancies complicated with AEDF in umbilical artery. As NRP-1 is known to promote sprouting angiogenesis, its down-regulation may be involved in the deficient vascular branching observed in FGR placentas suggesting the presence of an antiangiogenic state. Further studies may elucidate such a causal role and may lead to the development of novel diagnostic and therapeutic tools.
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Chen NN, He JR, Li WD, Kuang YS, Yuan MY, Liu XD, Zhang HZ, Hu SP, Xia HM, Qiu X. C1q and tumor necrosis factor-related protein 3 is present in human cord blood and is associated with fetal growth. Clin Chim Acta 2015; 453:67-70. [PMID: 26656444 DOI: 10.1016/j.cca.2015.11.031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Revised: 11/27/2015] [Accepted: 11/30/2015] [Indexed: 12/22/2022]
Abstract
BACKGROUND To determine the presence of C1q and tumor necrosis factor-related protein 3 (CTRP3) in cord blood and its relationship with fetal growth among Chinese newborns. METHODS This pilot study recruited 126 infants (small for gestational age [SGA], n=34; appropriate for gestational age [AGA], n=60; large for gestational age [LGA], n=32); cord blood CTRP3 levels were measured, and fetal growth parameters were collected. RESULTS Median (25-75th percentile) CTRP3 levels in the SGA, AGA, and LGA groups were 297.2 (236.4-360.2), 297.5 (261.0-369.9), and 368.6 (298.5-507.1) ng/ml, respectively (P=0.01). LGA infants had higher CTRP3 levels than AGA infants (multiple linear regression analysis; P=0.01). The CTRP3 levels were positively correlated with birth weight (r=0.25, P<0.01), Ponderal index (r=0.28, P<0.01), and placental weight (r=0.20, P=0.03) in the total study population. In the subgroup analysis, CTRP3 levels were negatively correlated with birth length z scores (r=-0.39, P=0.03) and were positively correlated with the Ponderal index (r=0.43, P=0.02) only in the SGA group; no other significant correlations were observed. The CTRP3 levels were similar between the sexes (P=NS). CONCLUSIONS CTRP3 is present in cord blood and might be involved in fetal growth.
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Affiliation(s)
- Nian-Nian Chen
- Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Jian-Rong He
- Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Wei-Dong Li
- Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Ya-Shu Kuang
- Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Ming-Yang Yuan
- Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Xiao-Dan Liu
- Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Hui-Zhu Zhang
- Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Shun-Ping Hu
- Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Hui-Min Xia
- Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Xiu Qiu
- Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
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Baka S, Malamitsi-Puchner A, Briana DD, Boutsikou M, Marmarinos A, Gourgiotis D, Boutsikou T. Adropin concentrations in term pregnancies with normal, restricted and increased fetal growth. J Matern Fetal Neonatal Med 2015; 29:2403-7. [PMID: 26490387 DOI: 10.3109/14767058.2015.1089861] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
OBJECTIVE To determine levels of adropin (implicated in insulin resistance and endothelial dysfunction) in intrauterine growth restricted (IUGR), large (LGA) and appropriate for gestational age (AGA) pregnancies. METHODS Cord-blood (UC) adropin and insulin concentrations were measured in 30 IUGR, 30 LGA and 20 AGA full-term infants and their mothers (MS). RESULTS No significant differences in adropin concentrations were observed between the three groups. In the IUGR group MS adropin was significantly decreased when neonates had higher birth weights [b = -0.003, 95% CI -0.006 to 0.0, p = 0.043]. In all groups, MS adropin levels were positively correlated with UC ones (r = 0.282, p = 0.011) and were significantly increased in female neonates [b = 0.977, 95% CI 0.122-1.832, p = 0.026]. In the LGA group, MS insulin was negatively correlated with UC adropin (r = -0.362 p = 0.049). CONCLUSIONS Increased maternal adropin levels in severe IUGR cases might represent a regulatory feedback mechanism against endothelial placental dysfunction. The positive correlation between maternal and umbilical cord adropin levels implies its transplacental transfer. Increased maternal adropin levels in female neonates could be attributed to interaction of adropin with fetal estrogens through vascular endothelial growth factor (VEGF). The negative correlation between maternal insulin and fetal adropin levels in the LGA group is probably attributed to their respective insulin resistance.
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Affiliation(s)
- Stavroula Baka
- a Department of Neonatology , Athens University Medical School , Athens , Greece and
| | | | - Despina D Briana
- a Department of Neonatology , Athens University Medical School , Athens , Greece and
| | - Maria Boutsikou
- a Department of Neonatology , Athens University Medical School , Athens , Greece and
| | - Antonios Marmarinos
- b Laboratory of Clinical Biochemistry-Molecular Diagnostics, 2nd Department of Pediatrics , Athens University Medical School , Athens , Greece
| | - Dimitrios Gourgiotis
- b Laboratory of Clinical Biochemistry-Molecular Diagnostics, 2nd Department of Pediatrics , Athens University Medical School , Athens , Greece
| | - Theodora Boutsikou
- a Department of Neonatology , Athens University Medical School , Athens , Greece and
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Increased ubiquitination and reduced plasma membrane trafficking of placental amino acid transporter SNAT-2 in human IUGR. Clin Sci (Lond) 2015; 129:1131-41. [PMID: 26374858 PMCID: PMC4614027 DOI: 10.1042/cs20150511] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 09/14/2015] [Indexed: 02/07/2023]
Abstract
Inhibition of placental mechanistic target of rapamycin (mTOR) signalling, which activates NEDD4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2) ubiquitin ligase leading to increased sodium-coupled neutral amino acid transporter 2 (SNAT-2) ubiquitination and removal from the syncytiotrophoblast plasma membrane may constitute a key mechanism underlying decreased placental amino acid transport in human IUGR. Placental amino acid transport is decreased in intrauterine growth restriction (IUGR); however, the underlying mechanisms remain largely unknown. We have shown that mechanistic target of rapamycin (mTOR) signalling regulates system A amino acid transport by modulating the ubiquitination and plasma membrane trafficking of sodium-coupled neutral amino acid transporter 2 (SNAT-2) in cultured primary human trophoblast cells. We hypothesize that IUGR is associated with (1) inhibition of placental mTORC1 and mTORC2 signalling pathways, (2) increased amino acid transporter ubiquitination in placental homogenates and (3) decreased protein expression of SNAT-2 in the syncytiotrophoblast microvillous plasma membrane (MVM). To test this hypothesis, we collected placental tissue and isolated MVM from women with pregnancies complicated by IUGR (n=25) and gestational age-matched women with appropriately grown control infants (n=19, birth weights between the twenty-fifth to seventy-fifth percentiles). The activity of mTORC1 and mTORC2 was decreased whereas the protein expression of the ubiquitin ligase NEDD4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2; +72%, P<0.0001) and the ubiquitination of SNAT-2 (+180%, P<0.05) were increased in homogenates of IUGR placentas. Furthermore, IUGR was associated with decreased system A amino acid transport activity (–72%, P<0.0001) and SNAT-1 (–42%, P<0.05) and SNAT-2 (–31%, P<0.05) protein expression in MVM. In summary, these findings are consistent with the possibility that decreased placental mTOR activity causes down-regulation of placental system A activity by shifting SNAT-2 trafficking towards proteasomal degradation, thereby contributing to decreased fetal amino acid availability and restricted fetal growth in IUGR.
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Dakouane-Giudicelli M, Brouillet S, Traboulsi W, Torre A, Vallat G, Si Nacer S, Vallée M, Feige JJ, Alfaidy N, de Mazancourt P. Inhibition of human placental endothelial cell proliferation and angiogenesis by netrin-4. Placenta 2015; 36:1260-5. [PMID: 26390805 DOI: 10.1016/j.placenta.2015.09.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 09/09/2015] [Accepted: 09/11/2015] [Indexed: 10/23/2022]
Abstract
INTRODUCTION Netrin-4 is a secreted member of the laminin-related protein family, known to be involved in axonal guidance and endothelial cell survival, proliferation, and migration. We have recently reported the cellular localization of netrin-4 and its receptor neogenin in human first trimester and term placenta. A strong expression of netrin-4 was observed in trophoblast and in endothelial cells, suggesting a potential role of this protein in placental angiogenesis. In relation to human pregnancy, it has been reported that circulating netrin-4 were increased in fetal umbilical cord blood of intrauterine growth restriction IUGR compared to normal pregnancy suggesting an adverse effect of this protein on placental and fetal development. The aim of this study was to determine the role of netrin-4 in placental angiogenesis. METHODS The effects of netrin-4 on proliferation, migration, tube-like organization, and spheroid sprouting of human placental microvascular endothelial cells (HPEC) were studied. RESULTS We demonstrated that netrin-4 inhibits HPEC proliferation, tube-like formation, migration and spheroid sprouting, suggesting a direct role of netrin-4 in the regulation of intra-villus angiogenesis. DISCUSSION This is the first report of an anti-angiogenic activity of netrin-4 in human placenta. This study brings new insights into netrin-4 roles in placental angiogenesis and suggests possible involvements of netrin-4 in angiogenesis-related pathologies such as IUGR.
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Affiliation(s)
- M Dakouane-Giudicelli
- Institut National de la Santé et de la Recherche Médicale, Unité 1179, Montigny Le Bretonneux, France; Université de Versailles Saint Quentin, En Yvelines, France.
| | - S Brouillet
- Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France; Université Grenoble-Alpes, 38000 Grenoble, France; Commissariat à l'Energie Atomique (CEA), iRTSV-Biology of Cancer and Infection, Grenoble, France; Centre Hospitalier Universitaire de Grenoble, Hôpital Couple-Enfant, Centre Clinique et Biologique d'Assistance Médicale à la Procréation, 38700 La Tronche, France
| | - W Traboulsi
- Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France
| | - A Torre
- Université de Versailles Saint Quentin, En Yvelines, France
| | - G Vallat
- Université de Versailles Saint Quentin, En Yvelines, France
| | - S Si Nacer
- Université de Versailles Saint Quentin, En Yvelines, France
| | - M Vallée
- Université de Versailles Saint Quentin, En Yvelines, France
| | - J J Feige
- Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France; Université Grenoble-Alpes, 38000 Grenoble, France; Commissariat à l'Energie Atomique (CEA), iRTSV-Biology of Cancer and Infection, Grenoble, France
| | - N Alfaidy
- Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France; Université Grenoble-Alpes, 38000 Grenoble, France; Commissariat à l'Energie Atomique (CEA), iRTSV-Biology of Cancer and Infection, Grenoble, France
| | - P de Mazancourt
- Institut National de la Santé et de la Recherche Médicale, Unité 1179, Montigny Le Bretonneux, France; Université de Versailles Saint Quentin, En Yvelines, France; AP-HP Hopital Ambroise Paré, Boulogne-Billancourt, France
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Story L, Sankaran S, Mullins E, Tan S, Russell G, Kumar S, Kyle P. Survival of pregnancies with small for gestational age detected before 24 weeks gestation. Eur J Obstet Gynecol Reprod Biol 2015; 188:100-3. [DOI: 10.1016/j.ejogrb.2015.02.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2014] [Revised: 01/17/2015] [Accepted: 02/06/2015] [Indexed: 10/24/2022]
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Rešić Karara J, Zekić Tomas S, Marušić J, Roje D, Kuzmić Prusac I. Fas and FasL expression in placentas complicated with intrauterine growth retardation with and without preeclampsia. J Matern Fetal Neonatal Med 2015; 29:1154-9. [PMID: 25909501 DOI: 10.3109/14767058.2015.1038702] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
OBJECTIVE To compare the level of Fas and FasL immunohistochemical expression in villous trophoblast (VT), extravillous trophoblast (EVT) cells, decidual cells (DC), endothelial cells (EC) of villous blood vessels and spiral arteries between the study groups of intrauterine growth retardation (IUGR) placentas with and without preeclampsia (PE). METHODS The study included 17 placentas from pregnancies complicated by IUGR + PE and 17 placentas from pregnancies complicated by idiopathic IUGR (I-IUGR). Seventeen placentas from normal pregnancies served as a control group. CD31 was used to detect endothelial cells (EC). Immunohistochemical expression of Fas and FasL was assessed in all examined parts of placenta using the semi-quantitative HSCORE method. RESULTS FasL expression was significantly higher in all examined parts of placenta in I-IUGR as compared to IUGR + PE and control group. Placentas with IUGR + PE had the significantly lowest expression of FasL in VT and EC of villi vessels. Expression of Fas did not differ significantly between the study groups. CONCLUSION Different expression of FasL in placentas from I-IUGR and IUGR + PE suggests that FasL probably has a different role in the etiology of these two syndromes.
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Affiliation(s)
| | - Sandra Zekić Tomas
- b Clinical Department of Pathology , Split University Hospital Center , Split , Croatia
| | | | - Damir Roje
- a Clinical Department of Gynecology and Obstetrics and
| | - Ivana Kuzmić Prusac
- b Clinical Department of Pathology , Split University Hospital Center , Split , Croatia
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Murthi P, Abumaree M, Kalionis B. Analysis of homeobox gene action may reveal novel angiogenic pathways in normal placental vasculature and in clinical pregnancy disorders associated with abnormal placental angiogenesis. Front Pharmacol 2014; 5:133. [PMID: 24926269 PMCID: PMC4045154 DOI: 10.3389/fphar.2014.00133] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Accepted: 05/14/2014] [Indexed: 11/13/2022] Open
Abstract
Homeobox genes are essential for both the development of the blood and lymphatic vascular systems, as well as for their maintenance in the adult. Homeobox genes comprise an important family of transcription factors, which are characterized by a well conserved DNA binding motif; the homeodomain. The specificity of the homeodomain allows the transcription factor to bind to the promoter regions of batteries of target genes and thereby regulates their expression. Target genes identified for homeodomain proteins have been shown to control fundamental cell processes such as proliferation, differentiation, and apoptosis. We and others have reported that homeobox genes are expressed in the placental vasculature, but our knowledge of their downstream target genes is limited. This review highlights the importance of studying the cellular and molecular mechanisms by which homeobox genes and their downstream targets may regulate important vascular cellular processes such as proliferation, migration, and endothelial tube formation, which are essential for placental vasculogenesis and angiogenesis. A better understanding of the molecular targets of homeobox genes may lead to new therapies for aberrant angiogenesis associated with clinically important pregnancy pathologies, including fetal growth restriction and preeclampsia.
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Affiliation(s)
- Padma Murthi
- Department of Perinatal Medicine, Pregnancy Research Centre, The Royal Women's Hospital Parkville, VIC, Australia ; Department of Obstetrics and Gynaecology, The University of Melbourne Parkville, VIC, Australia ; NorthWest Academic Centre, The University of Melbourne St. Albans, VIC, Australia
| | - Mohamed Abumaree
- College of Science and Health Professions, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences Riyadh, Saudi Arabia
| | - Bill Kalionis
- Department of Perinatal Medicine, Pregnancy Research Centre, The Royal Women's Hospital Parkville, VIC, Australia ; Department of Obstetrics and Gynaecology, The University of Melbourne Parkville, VIC, Australia
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Boutsikou T, Giotaki M, Gourgiotis D, Boutsikou M, Briana DD, Marmarinos A, Baka S, Hassiakos D, Malamitsi-Puchner A. Cord blood netrin-1 and -4 concentrations in term pregnancies with normal, restricted and increased fetal growth. J Matern Fetal Neonatal Med 2014; 27:1849-53. [PMID: 24716747 DOI: 10.3109/14767058.2014.905530] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE To determine levels of the possible angioregulatory molecules netrin-1 and -4, in intrauterine-growth-restricted (IUGR), large for gestational age (LGA) (both groups characterized by altered angiogenic mechanisms) and appropriate-for-gestational-age (AGA) pregnancies. METHODS Cord blood (UC) netrin-1 and -4 concentrations were measured in 30 IUGR, 30 LGA and 20 AGA infants and their mothers (MS). RESULTS Netrin-1 and -4 concentrations did not differ in all groups. UC netrin-4 increased with gestational age (b = 0.075, 95% CI 0.029-0.121, p = 0.002). In the IUGR group, MS netrin-4 decreased as birth-weight centiles increased [b = -0.058, 95% CI -0.112 to -0.004, p = 0.036]. In the LGA group, MS netrin-1 decreased with advanced gestational age [b = -0.063, 95% CI -0.105 to -0.022, p = 0.004]. In all cases, MS netrin-1 positively correlated with MS netrin-4 (r = 0.299, p = 0.007), while UC netrin-1 negatively correlated with UC netrin-4 (r = -0.239, p = 0.033). CONCLUSIONS Increased UC netrin-4 levels with advancing gestational age may reflect its effect on fetal development. Decreased maternal netrin-1 levels in the LGA group possibly represent a negative feedback mechanism against increased angiogenesis. Increased maternal netrin-4 levels in IUGR neonates may reflect in utero hypoxia, while the negative correlations between fetal netrin-1 and -4 levels may exert the dynamic balance between their angio- and anti-angiogenic properties.
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Affiliation(s)
- Theodora Boutsikou
- Department of Neonatology, Athens University Medical School , Athens , Greece and
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Jeong W, Song G, Bazer FW, Kim J. Insulin-like growth factor I induces proliferation and migration of porcine trophectoderm cells through multiple cell signaling pathways, including protooncogenic protein kinase 1 and mitogen-activated protein kinase. Mol Cell Endocrinol 2014; 384:175-84. [PMID: 24508636 DOI: 10.1016/j.mce.2014.01.023] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Revised: 01/08/2014] [Accepted: 01/31/2014] [Indexed: 11/27/2022]
Abstract
During early pregnancy, the developing conceptus is dependent upon a wide range of growth factors and nutrients that are secreted by or transported by uterine epithelia into the uterus at the maternal-conceptus interface for successful implantation and placentation. Among these factors, insulin-like growth factor-I (IGF-I) is known to play an important role in development of the early embryo and uterine endometrium. However, few studies have been conducted with pigs to determine IGF-I-induced functional effects on peri-implantation embryos such as activation of cell signaling cascades responsible for growth, proliferation and differentiation of cells of the conceptus. Therefore, the aim of this study was to analyze mRNA expression of endometrial IGF-I and its receptor, to examine the functional role of IGF-I on primary porcine trophectoderm (pTr) cells and to assess potential signaling pathways responsible for biological activities of IGF-1. In the present study, expression of endometrial type I IGF receptor (IGF-IR) mRNA increased significantly from Day 10 to Day 12 of pregnancy and the increase was greater for pregnant than cyclic gilts. Both IGF-I and IGF-IR mRNAs were abundant in endometrial luminal-, glandular epithelia, and stratum compactum stroma on Day 12 of pregnancy. In addition, IGF-I significantly induced phosphorylation of AKT1, ERK1/2 and RPS6 in a time- and concentration-dependent manner in pTr cells. Immunofluorescence microscopy revealed that IGF-I treated pTr cells exhibited increased abundance of phosphorylated (p)-AKT1 and p-ERK1/2 MAPK proteins in the nucleus and cytoplasm, and p-RPS6 proteins in the cytosol as compared to non-treated pTr cells. In the presence of the ERK1/2 MAPK inhibitor (U0126), IGF-I-induced AKT1 phosphorylation was not affected, whereas the PI3K inhibitor (LY294002) decreased IGF-I-induced phosphorylation of ERK1/2 and AKT1 proteins, and both the PI3K-AKT1 and ERK1/2 MAPK pathways were blocked by LY294002. Furthermore, IGF-I significantly stimulated both proliferation and migration of pTr cells, but these effects were blocked by P38 inhibitor (SB203580), U0126, MTOR inhibitor (rapamycin) and LY294002. Taken together, these results indicate that IGF-I coordinately regulates multiple cell signaling pathways including PI3K-AKT1-RPS6 and ERK1/2 MAPK signaling pathways that are critical to proliferation, migration and survival of trophectoderm cells during early pregnancy in pigs.
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Affiliation(s)
- Wooyoung Jeong
- Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Gwonhwa Song
- Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Fuller W Bazer
- Center for Animal Biotechnology and Genomics and Department of Animal Science, Texas A&M University, College Station, TX, USA
| | - Jinyoung Kim
- Department of Animal Resources Science, Dankook University, Cheonan, Republic of Korea.
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Borras D, Perales-Puchalt A, Ruiz Sacedón N, Perales A. Angiogenic growth factors in maternal and fetal serum in pregnancies complicated with intrauterine growth restriction. J OBSTET GYNAECOL 2014; 34:218-20. [DOI: 10.3109/01443615.2013.834304] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Roje D, Zekic Tomas S, Capkun V, Marusic J, Resic J, Kuzmic Prusac I. Asymmetrical fetal growth is not associated with altered trophoblast apoptotic activity in idiopathic intrauterine growth retardation. J Obstet Gynaecol Res 2013; 40:410-7. [DOI: 10.1111/jog.12170] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Accepted: 04/29/2013] [Indexed: 11/28/2022]
Affiliation(s)
- Damir Roje
- Clinical Hospital Center Split; Split Croatia
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Szentpéteri I, Rab A, Kornya L, Kovács P, Brubel R, Joó JG. Placental gene expression patterns of endoglin (CD105) in intrauterine growth restriction. J Matern Fetal Neonatal Med 2013; 27:350-4. [PMID: 23808956 DOI: 10.3109/14767058.2013.818125] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE In this study, we describe placental gene expression patterns of endoglin in pregnancies with intrauterine growth restriction (IUGR) compared to normal pregnancies. METHODS Placental samples were obtained from 101 pregnancies with IUGR using 140 normal pregnancy cases as control. Gene expression patterns and protein levels of the endoglin were compared between the two groups. For the gene expression analysis real-time PCR was applied, while for the estimation of placental protein level we performed Western analysis. RESULTS The placental endoglin gene was significantly overexpressed in the IUGR group versus the control group (Ln2(α): 1.69). The placental endoglin protein level proved to be significantly higher in case of IUGR (endoglin/β-actin ratio: 13.8 ± 2.3) versus the control cases (5.3 ± 1.1). The placental gene expression as well as the protein levels of endoglin showed no significant difference between female and male newborns. Concerning the placental gene expression and protein level, no significant difference was justified between the more (0-5 percentile) and less (5-10 percentile) severe cases of IUGR. CONCLUSION Increased placental gene expression of endoglin may result in vascular dysfunction leading to chronic fetal hypoxia, which may induce VEGF-A to stimulate angiogenesis. This can be explained as feed back response to restore fetal placental circulation.
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Affiliation(s)
- Imre Szentpéteri
- Praxis für Gynäkologie und Geburtshilfe und allgemeine Medizin , Wehingen, Baden-Württemberg , Germany
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Abstract
Preeclampsia, intrauterine growth retardation (IUGR), oligohydramnios, abortus, preterm birth and premature rupture of the membranes (PROM) are significant complications of pregnancy. Insufficient trophoblastic invasion plays an important role in the pathophysiology of pregnancy complications. Soluble human leukocyte antigen-gestation (HLA-G)1/G5 is a molecule associated with trophoblast invasion. When pregnancy complications are predicted early, strategies to prevent these complications can be implemented. The aim of this study was to investigate the relationship between first trimester maternal serum soluble HLA-G1/G5 levels and high-risk pregnancies. A total of 232 pregnant women were followed prospectively. Maternal blood samples were collected for determination of soluble HLA-G1/G5 levels at 11-14 weeks, during which routine serum free beta human chorionic gonadotropin (βhCG) and pregnancy associated plasma protein-A (PAPP-A) level determinations in addition to nuchal translucency (NT) measurements for Down's syndrome screening were done during 20-22 weeks gestation. The subjects were classified into normal pregnancy, preeclampsia, oligohydramnios, IUGR, preterm birth and PROM groups. First trimester maternal serum soluble HLA-G1/G5 levels were not significantly different between the groups. First trimester soluble HLA-G1/G5 did not predict high-risk pregnancies. Studies with larger number of cases are need to confirm our findings.
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Affiliation(s)
- Ismail Bıyık
- Department of Obstetrics and Gynecology, Karacabey State Hospital , Bursa , Turkey
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Myo-inositol metabolism in appropriately grown and growth-restricted fetuses: a proton magnetic resonance spectroscopy study. Eur J Obstet Gynecol Reprod Biol 2013; 170:77-81. [PMID: 23810059 DOI: 10.1016/j.ejogrb.2013.05.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2012] [Revised: 04/22/2013] [Accepted: 05/20/2013] [Indexed: 11/22/2022]
Abstract
OBJECTIVE Myo-inositol (Myo-ins) is a marker of neuroglial cells, being present in the astrocytes of brain tissue, but also functions as an osmolyte. Numbers of astrocytes are known to increase following injury to the brain. Growth-restricted fetuses are at increased risk of later neurodevelopmental impairments even in the absence of overt lesions and despite preserved/increased cerebral blood flow. This study aims to investigate brain Myo-ins metabolism in fetuses with intrauterine growth restriction (IUGR) and evidence of cerebral redistribution using magnetic resonance spectroscopy (MRS) at a short echo time. STUDY DESIGN Biometry and Doppler assessment of blood flow was assessed using ultrasound in 28 fetuses with IUGR and 47 appropriately grown control subjects. MRI was used to exclude overt brain injury. Proton magnetic resonance spectroscopy of the fetal brain was then performed at an echo time of 42 ms to examine the Myo-ins:Choline (Cho), Myo-ins:Creatine (Cr) and Cho:Cr ratios. RESULTS No alterations in brain Myo-ins:Cho, Myo-ins:Cr or Cho:Cr ratios were detected between appropriately grown and growth restricted fetuses. CONCLUSIONS IUGR is not associated with a measureable difference in brain myo-inositol ratios. This may be due to the protective effects of preserved cerebral blood flow in growth restriction and comparable astrocyte numbers when compared to controls.
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Szentpéteri I, Rab A, Kornya L, Kovács P, Joó JG. Gene expression patterns of vascular endothelial growth factor (VEGF-A) in human placenta from pregnancies with intrauterine growth restriction. J Matern Fetal Neonatal Med 2013; 26:984-9. [DOI: 10.3109/14767058.2013.766702] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Flisikowski K, Venhoranta H, Bauersachs S, Hänninen R, Fürst RW, Saalfrank A, Ulbrich SE, Taponen J, Lohi H, Wolf E, Kind A, Andersson M, Schnieke A. Truncation of MIMT1 Gene in the PEG3 Domain Leads to Major Changes in Placental Gene Expression and Stillbirth in Cattle1. Biol Reprod 2012; 87:140. [DOI: 10.1095/biolreprod.112.104240] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
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Nemec SF, Nemec U, Brugger PC, Bettelheim D, Weber M, Graham JM, Rimoin DL, Prayer D. Male genital abnormalities in intrauterine growth restriction. Prenat Diagn 2012; 32:427-31. [PMID: 22495637 DOI: 10.1002/pd.3831] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
OBJECTIVE Previous studies have shown a correlation between hypospadias and intrauterine growth restriction (IUGR), suggesting an association between placental insufficiency and abnormal genital development. This study sought to analyze the association of IUGR and genital abnormalities apparent on fetal magnetic resonance imaging (MRI). METHODS This retrospective study included 22 MRI scans of 20 male fetuses between 20 and 35 weeks of gestation presenting with IUGR. On MRI, penile length and testicular descent were evaluated. Student's t-testing and analysis of covariance were used to compare MRI penile length measurements with published normative data obtained from fetal ultrasonography (US) and MRI. McNemar testing was used to evaluate testicular descent in IUGR, compared with reported fetal MRI normative data. RESULTS The penile length in IUGR fetuses was shorter than in normal fetuses (p<0.001). Furthermore, six of 20 fetuses presented with a micropenis (2.5 SD below the mean value for age). Undescended testes were significantly more frequent in IUGR fetuses than in normal fetuses (p=0.004). CONCLUSION Our data confirm that abnormal fetal growth may be associated with penile shortening and, potentially, also undescended testes.
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Affiliation(s)
- Stefan F Nemec
- Department of Radiology, Division of Neuroradiology and Musculoskeletal Radiology, Medical University Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria.
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Selective and non-selective intrauterine growth restriction in twin pregnancies: high-risk factors and perinatal outcome. Arch Gynecol Obstet 2011; 285:973-8. [DOI: 10.1007/s00404-011-2119-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2011] [Accepted: 10/11/2011] [Indexed: 10/16/2022]
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