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1.
Am J Obstet Gynecol ; 226(2S): S886-S894, 2022 02.
Article in English | MEDLINE | ID: mdl-33007270

ABSTRACT

Preeclampsia is a major obstetrical complication with short- and long-term life-threatening consequences for both mother and child. Shallow cytotrophoblast invasion through the uterine decidua into the spiral arteries is implicated in the pathogenesis of preeclampsia, although the cause of deficient arterial invasion remains unknown. Research that is focused on the "soil"-the maternal decidua-highlights the importance of this poorly understood but influential uterine layer. Decidualization of endometrial cells regulates embryo invasion, which is essential for spiral artery remodeling and establishing the maternal-fetal interface. Exploration of the association between impaired decidualization and preeclampsia revealed suboptimal endometrial maturation and uterine natural killer cells present in the decidua before preeclampsia development. Furthermore, decidualization defects in the endometrium of women with severe preeclampsia, characterized by impaired cytotrophoblast invasion, were detected at the time of delivery and persisted 5 years after the affected pregnancy. Recently, a maternal deficiency of annexin A2 expression was found to influence aberrant decidualization and shallow cytotrophoblast invasion, suggesting that decidualization resistance, which is a defective endometrial cell differentiation during the menstrual cycle, could underlie shallow trophoblast invasion and the poor establishment of the maternal-fetal interface. Based on these findings, the transcriptional signature in the endometrium that promotes decidualization deficiency could be detected before (or after) conception. This would serve to identify women at risk of developing severe preeclampsia and aid the development of therapies focused on improving decidualization, perhaps also preventing severe preeclampsia. Here, we discuss decidualization deficiency as a contributor to the pathogenesis of pregnancy disorders with particular attention to severe preeclampsia. We also review current diagnostic strategies and discuss future directions in diagnostic methods based on decidualization.


Subject(s)
Decidua/physiopathology , Pre-Eclampsia/physiopathology , Annexin A2/genetics , Annexin A2/metabolism , Decidua/metabolism , Early Diagnosis , Endometrium/pathology , Female , Humans , Placentation/physiology , Pre-Eclampsia/diagnosis , Pregnancy , Trophoblasts/physiology
2.
Pediatr Dev Pathol ; 25(4): 452-457, 2022.
Article in English | MEDLINE | ID: mdl-35418257

ABSTRACT

Background: Chronic deciduitis is a chronic inflammatory placental disease. It is associated with severe perinatal complications, especially recurrent miscarriage, preterm birth, preterm labor, and preterm prelabor rupture of membranes.Methods: This study presents a detailed quantification of plasma cells and lymphocytes, and regards clinicopathological associations concerning different trimesters in 99 cases displaying chronic deciduitis with plasma cells (CD), 23 cases from the second trimester and 76 cases from the third trimester, respectively. The control group without CD consisted of matched placentas concerning the gestational weeks.Results: In every instance lymphocytes were more numerous than plasma cells. The mean value/highest score in ten high power fields were 50/321 for plasma cells, and 460/995 for lymphocytes, respectively. In the second trimester the scores for plasma cells were significantly higher than in the third trimester. In the third trimester preterm labor occurred significantly more often in cases with chronic deciduitis related to the control group (P < .05).Conclusion: In chronic deciduitis the plasma cell count is usually higher in the second compared to the third trimester. A brisk infiltration of the decidua with plasma cells could probably point to a more severe clinical manifestation and a higher risk for preterm labor and preterm birth.


Subject(s)
Chorioamnionitis , Decidua , Obstetric Labor, Premature , Plasma Cells , Premature Birth , Chorioamnionitis/pathology , Chronic Disease , Decidua/physiopathology , Female , Humans , Infant, Newborn , Obstetric Labor, Premature/pathology , Placenta/pathology , Plasma Cells/pathology , Pregnancy , Premature Birth/pathology
3.
J Biomed Sci ; 28(1): 3, 2021 Jan 04.
Article in English | MEDLINE | ID: mdl-33397374

ABSTRACT

BACKGROUND: Successful pregnancy is supported by a healthy maternal-fetal interfaceĀ (i.e., the decidual tissues) which holds the conceptus and safeguards it against stressors from the beginning of pregnancy. Any disturbance of this interface can presumably lead to the loss of pregnancy. The use of the immunosuppressive drug mycophenolic acid (MPA) should be discontinued in pregnancy given its abortive and embryotoxic effects. Direct teratogenic effects have been observed in mammalian embryos cultured in MPA, but the underlying mechanisms of abortion by MPA are less understood. METHODS: Decidual stromal cells isolated from human placentas are cultured in the presence of clinically relevant doses of MPA. Data regarding the effects of MPA on the proliferation and viability of decidua cultures are first analysed and then, molecular pathways contributing to these effects are unravelled. RESULTS: MPA treatment of decidual stromal cells results in loss of proliferation capacity and a decrease in the viability of decidua cultures. The molecular pathways involved in the effects of MPA on decidual stromal cells are a reduction in pre-rRNA synthesis and subsequent disruption of the nucleolus. The nucleolar stress stabilizes p53, which in turn, leads to a p21-mediated cell cycle arrest in late S and G2 phases, preventing the progression of the decidua cells into the mitosis. Furthermore, MPA does not induce apoptosis but activate mechanisms of autophagy and senescence in decidual stromal cells. CONCLUSION: The irreversible growth arrest of decidua cells, whose role in the maintenance of the pregnancy microenvironment is known, may be one cause of miscarriage in MPA treated pregnant women.


Subject(s)
Abortion, Spontaneous/chemically induced , Decidua/physiopathology , Immunosuppressive Agents/adverse effects , Mycophenolic Acid/adverse effects , Aging , Female , Humans , Placenta/physiopathology , Pregnancy
4.
Am J Obstet Gynecol ; 222(4): 376.e1-376.e17, 2020 04.
Article in English | MEDLINE | ID: mdl-31738896

ABSTRACT

BACKGROUND: Decidualization defects in the endometrium have been demonstrated at the time of delivery in women with severe preeclampsia and to linger for years, which suggests a maternal contributionĀ to the pathogenesis of this condition. Global transcriptional profiling reveals alterations in gene expression, which includes down-regulation of Annexin A2 in severe preeclampsia patients with decidualization resistance. OBJECTIVE: We investigated the functional role of Annexin A2 deficiency during endometrial decidualization and its potential contribution to shallow trophoblast invasion during implantation and subsequent placentation using inĀ vitro and inĀ vivo modeling. STUDY DESIGN: Annexin A2 gene and protein levels were assessed during inĀ vitro decidualization of human endometrial stromal cells isolated from biopsy specimens that were collected from women with previous severe preeclampsia (n=5) or normal obstetric outcomes (n=5). Next, Annexin A2 was inhibited with small interference RNA in control human endometrial stromal cells that were isolated from endometrial biopsy specimens (n=15) as an inĀ vitro model to analyze decidualization defects at the morphologic level and the secretion of prolactin and insulin-like growth binding protein-1. Annexin A2-inhibited cells were used to evaluate motility and promotion of embryo invasion. Decidualization and placentation defects of Annexin A2 deficiency were confirmed with the use of an Annexin A2-null mouse model. RESULTS: Annexin A2 gene and protein levels were down-regulated during inĀ vitro decidualization of human endometrial stromal cells from women with previous severe preeclampsia compared with control individuals. To assess its role in the endometrial stroma, we inhibited Annexin A2 expression and detected decidualization failure as evidenced by impaired morphologic transformation, which was associated with altered actin polymerization and low prolactin and insulin-like growth binding protein-1 secretions. Functionally, inĀ vitro models demonstrated that Annexin A2 inhibition failed to support embryo invasion. This finding was corroborated by reduced trophoblast spreading through human endometrial stromal cells, lack of motility of these cells, and reduced trophoblast invasion in the presence of conditioned media from Annexin A2-inhibited cells. Extending our discovery to an animal model, we detected that Annexin A2-null mice have a functional deficiency in decidualization and placentation that impairs fetal growth as a feature that is associated with severe preeclampsia. CONCLUSION: Together, inĀ vitro and inĀ vivo results suggest that endometrial defects in Annexin A2 expression impair decidualization of endometrial stromal cells as well as the uterine microenvironment that promotes embryo implantation and placentation. Our findings highlight the maternal contribution to the pathogenesis of severe preeclampsia and suggest that evaluation of Annexin A2 may provide a novel strategy to assess a woman's risk of experiencing this disease and perhaps discover therapeutic interventions to improve decidualization.


Subject(s)
Annexin A2/genetics , Annexin A2/metabolism , Decidua/physiopathology , Pre-Eclampsia/genetics , Actins/metabolism , Animals , Annexin A2/antagonists & inhibitors , Annexin A2/deficiency , Cell Movement , Cells, Cultured , Decidua/pathology , Disease Models, Animal , Embryo Implantation , Female , Gene Expression/drug effects , Humans , Insulin-Like Growth Factor Binding Protein 1/metabolism , Mice , Placentation/genetics , Pregnancy , Prolactin/metabolism , RNA, Small Interfering/pharmacology , Stromal Cells , Trophoblasts/physiology
5.
Arch Toxicol ; 93(12): 3601-3615, 2019 12.
Article in English | MEDLINE | ID: mdl-31642978

ABSTRACT

Women with hyperinsulinism and insulin resistance have reduced fertility, but the underlying mechanism is still poorly understood. Aberrant endometrial decidualization in early pregnancy was linked to pregnancy complications. In this study, we aimed to test whether elevated insulin levels compromise decidualization in early-stage pregnancy. C57BL/6JĀ mice in high insulin-exposed group were given a subcutaneous injection of recombinant insulin at a concentration of 0.05Ā IU daily. During decidualization in early pregnancy, serum levels of insulin, E2, P4, LH, FSH and blood glucose were significantly altered in mice treated with high insulin levels. The number of embryo implantation sites and endometrial decidual markers BMP2, ER, PR was significantly decreased by high insulin levels in vivo. Artificial decidual induction in primary mouse endometrial stromal cells and immortal human endometrial stromal cells line were all compromised after treated with 100Ā nmol/L insulin levels. All these results on flow cytometry, transmission electron microscopy and western blotting of Bax, Bcl2, cleaved Caspase3, cleaved PARP proteins level showed that decidual cells apoptosis was significantly decreased. Mitochondrial transmembrane potential also significantly increased by the influence of high insulin levels. PI3K and p-Akt were much higher after insulin exposure and the compromised decidualization by high insulin treatment was rescued by PI3K/Akt inhibitor LY294002 both in vitro and in vivo. In conclusion, we demonstrated that elevated insulin levels could compromise mice decidualization in early-stage pregnancy and PI3K/p-Akt-regulated apoptosis was essential for this role. It provides a clue for future investigation on compromised reproduction in women with hyperinsulinemia.


Subject(s)
Apoptosis/physiology , Endometrium/physiology , Insulin/blood , Uterus/pathology , Animals , Apoptosis/drug effects , Cell Line , Chromones/pharmacology , Decidua/drug effects , Decidua/pathology , Decidua/physiology , Decidua/physiopathology , Embryo Implantation , Endometrium/cytology , Endometrium/drug effects , Endometrium/physiopathology , Female , Humans , Insulin/adverse effects , Membrane Potential, Mitochondrial , Mice, Inbred C57BL , Morpholines/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Pregnancy , Proto-Oncogene Proteins c-akt/metabolism , Stromal Cells/drug effects , Stromal Cells/pathology
6.
Int J Mol Sci ; 20(21)2019 Oct 26.
Article in English | MEDLINE | ID: mdl-31717776

ABSTRACT

Recurrent pregnancy loss (RPL) represents an unresolved problem for contemporary gynecology and obstetrics. In fact, it is not only a relevant complication of pregnancy, but is also a significant reproductive disorder affecting around 5% of couples desiring a child. The current knowledge on RPL is largely incomplete, since nearly 50% of RPL cases are still classified as unexplained. Emerging evidence indicates that the endometrium is a key tissue involved in the correct immunologic dialogue between the mother and the conceptus, which is a condition essential for the proper establishment and maintenance of a successful pregnancy. The immunologic events occurring at the maternal-fetal interface within the endometrium in early pregnancy are extremely complex and involve a large array of immune cells and molecules with immunoregulatory properties. A growing body of experimental studies suggests that endometrial immune dysregulation could be responsible for several, if not many, cases of RPL of unknown origin. The present article reviews the major immunologic pathways, cells, and molecular determinants involved in the endometrial dysfunction observed with specific application to RPL.


Subject(s)
Abortion, Habitual/immunology , Decidua/immunology , Endometrium/immunology , Cytokines/metabolism , Decidua/physiopathology , Dendritic Cells/immunology , Embryo, Mammalian/immunology , Embryo, Mammalian/metabolism , Endometrium/physiopathology , Female , Humans , Killer Cells, Natural/immunology , Macrophages/immunology , Pregnancy , T-Lymphocytes, Regulatory/immunology
7.
Reproduction ; 156(6): 501-513, 2018 12.
Article in English | MEDLINE | ID: mdl-30328345

ABSTRACT

Adenosine monophosphate-activated protein kinase (AMPK) is a highly conserved heterotrimeric complex that acts as an intracellular energy sensor. Based on recent observations of AMPK expression in all structures of the female reproductive system, we hypothesized that AMPK is functionally required for maintaining fertility in the female. This hypothesis was tested by conditionally ablating the two catalytic alpha subunits of AMPK, Prkaa1 and Prkaa2, using Pgr-cre mice. After confirming the presence of PRKAA1, PRKAA2 and the active phospho-PRKAA1/2 in the gravid uterus by immunohistochemistry, control (Prkaa1/2 fl/fl ) and double conditional knockout mice (Prkaa1/2 d/d ) were placed into a six-month breeding trial. While the first litter size was comparable between Prkaa1/2 fl/fl and Prkaa1/2 d/d female mice (P = 0.8619), the size of all subsequent litters was dramatically reduced in Prkaa1/2 d/d female mice (P = 0.0015). All Prkaa1/2 d/d female mice experienced premature reproductive senescence or dystocia by the fourth parity. This phenotype manifested despite no difference in estrous cycle length, ovarian histology in young and old nulliparous or multiparous animals, mid-gestation serum progesterone levels or uterine expression of Esr1 or Pgr between Prkaa1/2 fl/fl and Prkaa1/2 d/d female mice suggesting that the hypothalamic-pituitary-ovary axis remained unaffected by PRKAA1/2 deficiency. However, an evaluation of uterine histology from multiparous animals identified extensive endometrial fibrosis and disorganized stromal-glandular architecture indicative of endometritis, a condition that causes subfertility or infertility in most mammals. Interestingly, Prkaa1/2 d/d female mice failed to undergo artificial decidualization. Collectively, these findings suggest that AMPK plays an essential role in endometrial regeneration following parturition and tissue remodeling that accompanies decidualization.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Endometritis/enzymology , Endometrium/enzymology , Fertility , Regeneration , Reproduction , AMP-Activated Protein Kinases/deficiency , AMP-Activated Protein Kinases/genetics , Animals , Decidua/enzymology , Decidua/pathology , Decidua/physiopathology , Dystocia/enzymology , Dystocia/genetics , Dystocia/physiopathology , Endometritis/genetics , Endometritis/pathology , Endometritis/physiopathology , Endometrium/pathology , Endometrium/physiopathology , Female , Fibrosis , Litter Size , Mice, Knockout , Parity , Pregnancy
8.
Clin Obstet Gynecol ; 61(4): 743-754, 2018 12.
Article in English | MEDLINE | ID: mdl-30299280

ABSTRACT

Current findings continue to support the concept of a biologically defective decidua rather than a primarily abnormally invasive trophoblast. Prior cesarean sections increase the risk of placenta previa and both adherent and invasive placenta accreta, suggesting that the endometrial/decidual defect following the iatrogenic creation of a uterine myometrium scar has an adverse effect on early implantation. Preferential attachment of the blastocyst to scar tissue facilitates abnormally deep invasion of trophoblastic cells and interactions with the radial and arcuate arteries. Subsequent high velocity maternal arterial inflow into the placenta creates large lacunae, destroying the normal cotyledonary arrangement of the villi.


Subject(s)
Cicatrix/physiopathology , Decidua/physiopathology , Myometrium/physiopathology , Placenta Accreta/physiopathology , Placental Circulation , Trophoblasts , Cesarean Section/statistics & numerical data , Female , Humans , Myometrium/diagnostic imaging , Myometrium/pathology , Placenta Accreta/diagnostic imaging , Placenta Accreta/epidemiology , Placenta Accreta/pathology , Placenta Previa/epidemiology , Pregnancy , Ultrasonography, Prenatal , Uterine Artery
9.
Mol Hum Reprod ; 23(7): 509-519, 2017 07 01.
Article in English | MEDLINE | ID: mdl-28402512

ABSTRACT

STUDY QUESTION: What is the impact of chronic hypertension on placental development, fetal growth and maternal outcome in the stroke-prone spontaneously hypertensive rat (SHRSP)? SUMMARY ANSWER: SHRSP showed an impaired remodeling of the spiral arteries and abnormal pattern of trophoblast invasion during placentation, which were associated with subsequent maternal glomerular injury and increased baseline hypertension as well as placental insufficiency and asymmetric fetal growth restriction (FGR). WHAT IS KNOWN ALREADY: A hallmark in the pathogenesis of preeclampsia (PE) is abnormal placentation with defective remodeling of the spiral arteries preceding the onset of the maternal syndrome. Pregnancies affected by chronic hypertension display an increased risk for PE, often associated with poor maternal and fetal outcomes. However, the impact of chronic hypertension on the placentation process as well as the nature of the factors promoting the development of PE in pregnant hypertensive women remain elusive. STUDY DESIGN, SIZE, DURATION: Timed pregnancies [n = 5] were established by mating 10-12-week-old SHRSP and Wistar Kyoto (WKY, normotensive controls) females with congenic males. Maternal systolic blood pressures (SBPs) were recorded pre-mating, throughout pregnancy (GD1-19) and post-partum by the tail-cuff method. On selected dates, 24 h urine- and blood samples were collected, and animals were euthanized for isolation of implantation sites and kidneys for morphometrical analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 24 h proteinuria and the albumin:creatinine ratio were used for evaluation of maternal renal function. Renal injury was assessed on periodic acid Schiff, Masson's trichrome and Sirius red stainings. Placental and fetal weights were recorded on gestation day (GD)18 and GD20, followed by determination of fetal cephalization indexes and developmental stage, according to the Witschi scale. Morphometric analyses of placental development were conducted on hematoxylin-eosin stained tissue sections collected on GD14 and GD18, and complemented with immunohistochemical evaluation of isolectin B4 binding for assessment of placental vascularization. Analyses of vascular wall alpha actin content, perforin-positive natural killer (NK) cells and cytokeratin expression by immunohistochemistry were used for evaluation of spiral artery remodeling and trophoblast invasion. MAIN RESULTS AND THE ROLE OF CHANCE: SHRSP females presented significantly increased SBP records from GD13 to GD17 (SBPGD13 = 183.9 Ā± 3.9 mmHg, P < 0.005 versus baseline) and increased proteinuria at GD18 (P < 0.01 versus WKY). Histological examination of GD18 kidneys revealed glomerular enlargement and mesangial matrix expansion, which were not evident in pregnant WKY or age-matched virgin SHRSP. At GD20, SHRSP displayed a significant reduction of placental mass (P < 0.01 versus WKY) and signs of placental insufficiency (i.e. hypertrophy and reduced branching morphogenesis of the labyrinth layer), associated with decreased offspring weights and increased cephalization index (both P < 0.001 versus WKY) indicating asymmetric FGR. Notably, SHRSP placentas displayed an incomplete remodeling of spiral arteries starting as early as GD14, with luminal narrowing and reduced densities of perivascular NK cells followed by decreased infiltration of endovascular trophoblasts at GD18. LARGE SCALE DATA: n/a. LIMITATIONS, REASONS FOR CAUTION: A pitfall of the present study is the differences in the blood pressure profiles between rats and humans (i.e. unlike pregnancies affected by PE, blood pressure in SHRSP and other hypertensive rat models decreases pre-delivery), which limits extrapolation of the results. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide new insights on the role of chronic hypertension as a risk factor for PE by interfering with early events during the placentation process. The SHRSP strain represents an attractive model for further studies aimed at addressing the relative contribution of intrinsic (i.e. placental) and extrinsic (i.e. decidual/vascular) factors to defective spiral artery remodeling in pregnancies affected by PE. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by research grants from FundaciĆ³n Florencio Fiorini to G.B., from CharitĆ© Stiftung to S.M.B. and University of Buenos Aires (UBACyt) to J.T. The authors have no competing interests to declare.


Subject(s)
Fetal Growth Retardation/physiopathology , Pre-Eclampsia/physiopathology , Proteinuria/physiopathology , Stroke/physiopathology , Trophoblasts/pathology , Actins/genetics , Actins/metabolism , Animals , Biomarkers , Decidua/metabolism , Decidua/pathology , Decidua/physiopathology , Female , Fetal Growth Retardation/metabolism , Fetal Growth Retardation/pathology , Fetus , Gene Expression , Keratins/genetics , Keratins/metabolism , Kidney/metabolism , Kidney/pathology , Kidney/physiopathology , Placentation , Pre-Eclampsia/metabolism , Pre-Eclampsia/pathology , Pregnancy , Proteinuria/metabolism , Proteinuria/pathology , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Stroke/metabolism , Stroke/pathology , Trophoblasts/metabolism , Uterine Artery/metabolism , Uterine Artery/pathology , Uterine Artery/physiopathology , Vascular Remodeling
10.
Adv Exp Med Biol ; 887: 143-55, 2015.
Article in English | MEDLINE | ID: mdl-26662990

ABSTRACT

Embryo implantation requires a reciprocal interaction between the blastocyst and endometrium and is associated with complex regulatory mechanisms. Since their discovery, microRNAs became prominent candidates providing missing links for many biological pathways. In recent years, microRNAs were implicated as one of the important players in regulation of various biological and physiological endometrial related processes. This chapter aims to present recent knowledge pertaining to the diverse aspects of microRNAs in the embryo-endometrial relationship. We will focus on the role of microRNAs in decidualization and their part in natural and stimulated cycles. Next, we will present recent studies deliberating the role of microRNAs in recurrent pregnancy loss and in the important phenomenon of recurrent implantation failure. Lastly, demonstrating an important aspect of embryo implantation and invasion, we will outline few microRNA related shared pathways of implantation and carcinogenesis.


Subject(s)
Embryo Implantation , Embryo Loss/genetics , Embryo Loss/physiopathology , Endometrium/physiopathology , MicroRNAs/genetics , Abortion, Habitual , Animals , Decidua/metabolism , Decidua/physiopathology , Endometrium/metabolism , Female , Gene Expression Regulation, Developmental , Humans , MicroRNAs/metabolism , Pregnancy
11.
Am J Obstet Gynecol ; 210(6): 545.e1-6, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24370690

ABSTRACT

OBJECTIVE: Women with a history of preeclampsia (PE) have an increased prevalence of cardiometabolic, cardiovascular, and prothrombotic risk factors. Remotely, these women are at increased risk of developing cardiovascular and thrombotic disease. Decidual vasculopathy (DV) describes vascular lesions in the maternal spiral arteries of the uterus, which are found in approximately 40-60% of women with PE. DV is thought to be related to atherosclerosis because of their morphological similarity. The aim of this study was to investigate the association of cardiovascular and thrombogenic risk factors with DV in women with a history of PE. STUDY DESIGN: We retrospectively analyzed the cardiovascular and thrombogenic risk of women with a history of PE, comparing cases with DV (nĀ = 95) with cases without the lesions (nĀ = 81) 7 months after the index pregnancy. Data from a cohort of patients with a history of PE were matched with records from our pathology database. RESULTS: The DV group showed higher diastolic blood pressure (73 vs 70 mm Hg, PĀ = .031), lower left ventricular stroke volume (71 vs 76Ā mL, PĀ = .032), higher total peripheral vascular resistance (1546 vs 1385, PĀ = .009), and a higher percentage of low plasma volume (34% vs 19%, PĀ = .030). DV did not relate to other cardiovascular parameters, urinary protein, body mass index, lipid or glucose metabolism parameters, or thrombophilia. CONCLUSION: In this study, in women with a history of PE, cases with DV had increased cardiovascular risk, exhibiting circulatory alterations, suggesting reduced venous reserves and elevated arterial tone, without metabolic or thrombophilic disturbances.


Subject(s)
Cardiovascular Diseases , Decidua/blood supply , Placenta/pathology , Pre-Eclampsia/pathology , Thrombophilia/diagnosis , Adult , Body Mass Index , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/physiopathology , Cohort Studies , Decidua/physiopathology , Echocardiography , Female , Humans , Pre-Eclampsia/physiopathology , Pregnancy , Retrospective Studies , Risk Assessment , Risk Factors
12.
Reprod Biomed Online ; 27(2): 172-5, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23664817

ABSTRACT

The aim of the present study was to evaluate whether ovarian stimulation could induce embryo implantation dysfunction in mice and to explore the possible mechanisms involved. Ovarian stimulation was performed with intraperitoneal injections of 0, 2.5, 5.0, 7.5 and 10.0 IU pregnant mare serum gonadotrophin followed by the same dose of human chorionic gonadotrophin 48h later. A dose-dependent implantation defect in stimulated mice was demonstrated, which can be mainly explained by premature luteolysis and secondary endometrial changes induced by an imbalance in oestradiol and progesterone.


Subject(s)
Chorionic Gonadotropin/adverse effects , Embryo Implantation, Delayed , Endometrium/drug effects , Gonadotropins, Equine/adverse effects , Infertility, Female/etiology , Luteolysis/drug effects , Ovulation Induction/adverse effects , Animals , Chorionic Gonadotropin/administration & dosage , Decidua/drug effects , Decidua/physiopathology , Dose-Response Relationship, Drug , Endometrium/physiopathology , Estradiol/blood , Female , Fertility Agents, Female/administration & dosage , Fertility Agents, Female/adverse effects , Gonadotropins, Equine/administration & dosage , Humans , Infertility, Female/blood , Infertility, Female/physiopathology , Mice , Placentation/drug effects , Pregnancy , Progesterone/blood , Severity of Illness Index , Uterine Diseases/blood , Uterine Diseases/chemically induced , Uterine Diseases/physiopathology
13.
Mol Cell Endocrinol ; 540: 111509, 2022 01 15.
Article in English | MEDLINE | ID: mdl-34801669

ABSTRACT

Preeclampsia (PE), a hypertensive complication in pregnancy, is a major contributor to maternal and fetal morbidity and mortality. PE has long been regarded a heterogeneous disorder with a pathogenesis that involves multiple genes and factors. Glucose transporter 1 (GLUT1) is a central rate-limiting pump that is involved in glucose uptake and subsequent utilization. Our previous RNA-seq results demonstrated GLUT1 was significantly downregulated in deciduas from patients with severe PE. Therefore, in this study, we aimed to explore the role of GLUT1 in the occurrence of PE. Our data showed that mRNA and protein levels of GLUT1 were significantly downregulated in the deciduas from patients with severe PE. Additionally, GLUT1 levels were substantially upregulated in human endometrial stromal cells (HESCs) during in vitro decidualization. Moreover, GLUT1 knockdown significantly reduced the mRNA levels of decidualization markers (IGFBP1 and PRL) and aerobic glycolysis-related genes (LDHA and MCT4), as well as decreased glucose uptake and lactate production. Furthermore, upon GLUT1 knockdown, the levels of apoptotic genes P53, P21, and BAX increased whereas the level of BCL2 decreased. Target prediction results and luciferase analysis showed that GLUT1 is one of the targets of miR-140-5p, which is partly responsible for downregulated GLUT1 levels. Collectively, these results demonstrate that GLUT1 exerts a pivotal role in human decidualization by participating in glycolysis, and that GLUT1 deficiency may trigger aberrant glycolysis, thereby leading to destructive decidualization that may impede blastocyst implantation, trophoblast invasion, and subsequent placental development, which are associated with PE. Taken together, these data suggest that GLUT1 might be a promising target for PE therapy.


Subject(s)
Embryo Implantation/genetics , Glucose Transporter Type 1/genetics , Pre-Eclampsia/genetics , Adult , Case-Control Studies , Cells, Cultured , Decidua/metabolism , Decidua/physiopathology , Female , Glucose Transporter Type 1/metabolism , Glycolysis/genetics , Humans , MicroRNAs/physiology , Pre-Eclampsia/physiopathology , Pregnancy
14.
Hypertens Res ; 44(3): 318-324, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33093639

ABSTRACT

Defective decidual function contributes to the pathogenesis of preeclampsia. However, the precise mechanism of defective decidua during preeclampsia has not been characterized. During decidualization, endometrial stromal cells undergo phenotypic changes that are consistent with mesenchymal-epithelial transition (MET). cGMP-dependent kinase protein I (PKGI)/VASP signaling is important in cell motility proliferation, differentiation and cell adhesion. To investigate this aim, we analyzed PKGI levels, phosphorylated VASP protein levels, and eNOS and sGC protein expression levels during pregnancy complicated by preeclampsia, which indicated that PKGI/VASP signaling function is decreased by the condition. Moreover, we evaluated the differential expression of genes that regulate MET in the decidua resulting from preeclampsia and healthy pregnancies. We discovered that vimentin mRNA levels are decreased in the decidua of preeclampsia, which indicates that excessive MET occurs in the decidua of preeclampsia pregnancies. A fundamental developmental MET program occurred in response to signaling pathways. These results suggest the important role of decreased PKGI/VASP signaling during excessive MET in the pathogenesis of preeclampsia.


Subject(s)
Cyclic GMP-Dependent Protein Kinase Type I , Decidua , Pre-Eclampsia , Cyclic GMP-Dependent Protein Kinase Type I/metabolism , Decidua/physiopathology , Female , Humans , Pre-Eclampsia/physiopathology , Pregnancy
15.
Reprod Sci ; 28(4): 1185-1193, 2021 04.
Article in English | MEDLINE | ID: mdl-33237514

ABSTRACT

After undergoing remodeling, uterine spiral arteries turn into wide, flexible tubes, with low resistance. If remodeling does not occur, spontaneous abortions, intrauterine growth restriction, and pregnancy-related hypertensive disorders can ensue. Arterial transformation begins at a very early gestational stage; however, second quarter pregnancy histopathological samples have yet to pinpoint the exact moment when abnormal remodeling transpires. We examined 100 samples, taken from consecutive abortions at 12-23 gestational weeks. Following Pijnenborg and Smith guidelines, blinded pathologists analyzed clinical data on remodeling stages. Lab results showed that arterial remodeling is not synchronic in all vessels; a single sample can include various remodeling stages; neither is remodeling homogenous in a single vessel: change may be occurring in one part of the vessel, but not in another. To our knowledge, no one has published this finding. In the examined age group, Smith stage IV predominates; around week 14, substantial muscle and endothelium loss takes place. After week 17, endovascular or fibrin trophoblast does not usually occur. Although scant consensus exists on what defines preeclampsia etiology, it is clear that it involves abnormal remodeling in decidua vessels. Improved understanding requires further knowledge on both the physiological and pathological aspects of the remodeling process. We observed that muscle and endothelial tissues disappear from weeks 14-17, after which time reendothelization predominates. We list the expected proportion of spiral artery changes for each gestational age which, to date, has not been available.


Subject(s)
Placenta/physiopathology , Uterine Artery/physiopathology , Vascular Remodeling/physiology , Adolescent , Adult , Decidua/pathology , Decidua/physiopathology , Female , Humans , Placenta/pathology , Pre-Eclampsia/pathology , Pre-Eclampsia/physiopathology , Pregnancy , Pregnancy Trimester, Second , Trophoblasts/pathology , Uterine Artery/pathology , Young Adult
16.
Reprod Sci ; 28(2): 406-415, 2021 02.
Article in English | MEDLINE | ID: mdl-32845508

ABSTRACT

Repeated implantation failure (RIF) is a common endocrine disease that causes female infertility and the etiology is unknown. The abnormal expression of key proteins and hormones at the maternal-fetal interface affected the maternal-fetal communication and leads to adverse pregnancy outcomes. The expression of anti-Mullerian hormone (AMH) and AMH receptor II (AMHRII) was observed in the endometrium. This study aimed to investigate the expression of AMH and AMHRII at the human endometrium, decidual tissue, and blastocyst. Furthermore, the expression of AMH and AMHRII were examined in the RIF patients using immunohistochemistry and quantitative real-time PCR to test the AMHRII expression. The results demonstrated that AMH and AMHRII were present in healthy endometrium and AMHRII was highly expressed in mid-luteal phase. In addition, AMHRII expression was detected throughout the pregnancy and AMHRII's highest expression was in the second trimester. AMHRII was expressed in the blastocysts; however, AMH was not observed. The positive expression rate for AMHRII was significantly higher in the endometrium from RIF. Estrogen receptor (ER), insulin-like growth factor binding protein 1(IGFBP1), and prolactin (PRL) were significantly less expressed in RIF with high expression of AMHRII. The apoptosis was significantly higher in patients with high expression of AMHRII than in patients with normal expression of AMHRII. Our data suggests that AMHRII had an effect on RIF via the AMH and AMHRII signaling pathway. It participated in the development of RIF by interfering with endometrial decidualization and apoptosis.


Subject(s)
Anti-Mullerian Hormone/genetics , Embryo Implantation/genetics , Embryo Transfer/adverse effects , Endometrium/metabolism , Fertilization in Vitro/adverse effects , Genetic Variation , Infertility/therapy , Receptors, Peptide/genetics , Receptors, Transforming Growth Factor beta/genetics , Adult , Anti-Mullerian Hormone/metabolism , Apoptosis , Blastocyst/metabolism , Blastocyst/pathology , Case-Control Studies , Decidua/metabolism , Decidua/physiopathology , Endometrium/physiopathology , Female , Humans , Infertility/diagnosis , Infertility/physiopathology , Pregnancy , Receptors, Peptide/metabolism , Receptors, Transforming Growth Factor beta/metabolism , Risk Factors , Signal Transduction , Treatment Failure
17.
Int Immunopharmacol ; 90: 107118, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33191177

ABSTRACT

Recurrent pregnancy loss (RPL) is a prominent reproductive disease that distresses about 2%-5% of couples. RPL is the loss of two or more successive spontaneous pregnancies prior to the 20th week of embryo development. The commencement of pregnancy necessitates implantation of the embryo into responsive maternal decidua synchronized with the process of placentation, decidual and myometrial trophoblast incursion as well as refashioning of spiral blood arteries of uterus. The collapse of any of the processes fundamental for pregnancy success may result into an array of pregnancy problems including spontaneous pregnancy loss. Endometrium of human female manufactures an extensive range of cytokines during the proliferative and secretory stage of the menstrual cycle. These endometrial cytokines are thought as major players for making the uterus ready for embryo implantation and placental development during pregnancy. Decidual cytokines regulate the invasion of trophoblast and remodeling of spiral arteries as well as take part in immune suppression to accomplish the pregnancy. Deterrence of maternal rejection of embryo needs a regulated milieu, which takes place essentially at the embryo-maternal interface and the tissues of the uterus. The reasons of RPL remain anonymous in a large number of cases that lead to difficulties in management and severe trauma in couples. Cytokine modulatory therapies have been shown promising for preventing RPL. Further study of novel factors is wanted to establish more effective RPL treatment protocols. The present study aims to review the outcome of cytokine breach at materno-embryonic interface and the efficacy of cytokine modulatory therapies in RPL.


Subject(s)
Abortion, Habitual/metabolism , Cytokines/metabolism , Decidua/metabolism , Maternal-Fetal Exchange , T-Lymphocytes, Helper-Inducer/metabolism , T-Lymphocytes, Regulatory/metabolism , Abortion, Habitual/immunology , Abortion, Habitual/physiopathology , Abortion, Habitual/prevention & control , Animals , Decidua/drug effects , Decidua/immunology , Decidua/physiopathology , Female , Humans , Immunologic Factors/therapeutic use , Phenotype , Pregnancy , Signal Transduction , T-Lymphocytes, Helper-Inducer/drug effects , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology
18.
Ultrasound Obstet Gynecol ; 36(3): 362-7, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20603859

ABSTRACT

OBJECTIVES: To describe the sonographic findings in the decidua basalis layer in spontaneous early pregnancy loss and to compare them with those in normal pregnancy. METHODS: We reviewed 119 scans at 4-10 weeks' gestation from 110 patients who miscarried clinically at less than 13 weeks' gestation and 132 scans also at 4-10 weeks from 98 patients who had normal uncomplicated term pregnancies. The thickness and echogenicity of the decidua basalis layer were compared between pregnancies which suffered early loss and normal controls. RESULTS: Relative thinning of the decidua basalis was observed in cases of early pregnancy loss from 5-6 weeks onwards when compared with normal pregnancies. In embryonic pregnancies that subsequently miscarried, the decidua basalis did not show the rising trend in thickness that was observed in normal pregnancies. Shortly before and after embryonic demise, the decidua appeared relatively more echogenic compared with that in normal pregnancy and the placenta showed areas of hypoechogenicity. Embryonic demise was followed by disorganization of the decidual layer, which became difficult to recognize. Pregnancy with an empty sac showed a more gradual trend in the thinning of the decidua basalis, but the uniformity and echogenicity of the layer appeared to be relatively better preserved with time. CONCLUSION: The decidua basalis layer in pregnancies that are destined to miscarry in the first trimester differs sonographically from that in normal pregnancies. The sonographic differences are suggestive of a defective decidual-placental complex resulting from deficient trophoblastic invasion.


Subject(s)
Abortion, Spontaneous/diagnostic imaging , Decidua/diagnostic imaging , Placenta/diagnostic imaging , Trophoblasts/diagnostic imaging , Abortion, Spontaneous/physiopathology , Adult , Decidua/physiopathology , Female , Gestational Age , Humans , Placenta/physiopathology , Pregnancy , Pregnancy Trimester, First , Trophoblasts/physiology , Ultrasonography, Prenatal
19.
Nat Rev Endocrinol ; 16(9): 479-494, 2020 09.
Article in English | MEDLINE | ID: mdl-32601352

ABSTRACT

Pre-eclampsia and fetal growth restriction arise from disorders of placental development and have some shared mechanistic features. Initiation is often rooted in the maldevelopment of a maternal-placental blood supply capable of providing for the growth requirements of the fetus in later pregnancy, without exerting undue stress on maternal body systems. Here, we review normal development of a placental bed with a safe and adequate blood supply and a villous placenta-blood interface from which nutrients and oxygen can be extracted for the growing fetus. We consider disease mechanisms that are intrinsic to the maternal environment, the placenta or the interaction between the two. Systemic signalling from the endocrine placenta targets the maternal endothelium and multiple organs to adjust metabolism for an optimal pregnancy and later lactation. This signalling capacity is skewed when placental damage occurs and can deliver a dangerous pathogenic stimulus. We discuss the placental secretome including glycoproteins, microRNAs and extracellular vesicles as potential biomarkers of disease. Angiomodulatory mediators, currently the only effective biomarkers, are discussed alongside non-invasive imaging approaches to the prediction of disease risk. Identifying the signs of impending pathology early enough to intervene and ameliorate disease in later pregnancy remains a complex and challenging objective.


Subject(s)
Fetal Growth Retardation/physiopathology , Placentation/physiology , Pre-Eclampsia/physiopathology , Pregnancy Complications/physiopathology , Biomarkers , Decidua/physiopathology , Embryonic Development , Endometrium/physiopathology , Female , Fetal Development , Fetus/blood supply , Humans , Placenta/blood supply , Placenta Diseases/physiopathology , Pregnancy , Signal Transduction , Trophoblasts/physiology
20.
J Gynecol Obstet Hum Reprod ; 49(6): 101705, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32018041

ABSTRACT

Gap junction form channels between the cells and facilitate the function of cellular cross talk. Connexins, the gap junction proteins play an essential role in female reproductive health and its expression anomalies are correlated with female reproductive disorders like polycystic ovarian syndrome, recurrent miscarriage, pre-term birth and endometriosis. Endometriosis is a chronic gynecologic disorder caused by ectopic endometrial lesions growing outside the uterine cavity. Embryonic implantation is adversely affected in case of endometriosis leading to infertility. Endometriosis also interferes with ovulatory functions, reduces fertilization and impaires blastocyst implantation. There lies a lacunae in understanding of the role of gap junctions protein connexins in endometriosis. Therefore, this study discusses the role of connexins in improving female fertility by taming the processes of oogenesis, germ line development, uterine receptivity, placental growth, implantation, decidualization and concludes by focusing the role of connexins in endometriosis.


Subject(s)
Connexins/physiology , Endometriosis/physiopathology , Genitalia, Female/physiopathology , Decidua/physiopathology , Embryo Implantation/physiology , Endometriosis/complications , Endometriosis/pathology , Endometrium/physiopathology , Female , Gap Junctions/physiology , Humans , Infertility, Female/etiology , Infertility, Female/physiopathology , Infertility, Female/therapy , Oogenesis/physiology , Ovulation/physiology , Pregnancy , Uterus/physiopathology
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