Temporal Changes of the Endothelin System in Human Cytotrophoblasts During the First Trimester of Pregnancy

The first trimester of pregnancy is characterized by continuous proliferation, invasion and differentiation of cytotrophoblasts. These processes are precisely controlled both, in space and time by molecules such as endothelin-1 (ET-1). ET-1 is expressed in human first trimester trophoblast and is known to stimulate cytotrophoblast proliferation through endothelin A and B receptor subtypes (ETA and ETB), and cytotrophoblast invasion through ETB. However, temporal changes of the ET system during the first trimester of pregnancy have not been previously studied. This study tested the hypothesis that ET-1 release, ETA and ETB expression are increased towards the end of the first trimester of pregnancy (weeks 10-12 vs. weeks 6-9), resulting in increased cytotrophoblast proliferation and invasion. Tissue samples were obtained from 17 surgical pregnancy interruptions (week 6-9: n=9; week 10-12: n=8). After cytotrophoblast isolation, the invasive and proliferative phenotypes were immune-separated by an α6-integrin antibody. Both proliferative and invasive cytotrophoblasts were cultured separately on plastic or Matrigel for 24 h. ET-1 release into the culture medium of both cytotrophoblast subtypes was measured by radioimmunoassay. ETA and ETB mRNA expression was measured by RT-PCR, and the ET-1 effect on cytotrophoblast proliferation and invasion was determined using proliferation and invasion assays, respectively. ET-1 release increased from early to late first trimester of pregnancy in both proliferative (1.8-4.5 fold) and invasive cytotrophoblasts (9.3-28 fold), especially when cultured on Matrigel. This was paralleled by less ETB mRNA on invasive cytotrophoblasts independent of the time period in first trimester, whereas ETA expression was similar on proliferative an invasive cytotrophoblasts. Proliferation and invasion of cytotrophoblasts under control conditions decreased from early to late first trimester. ET-1 stimulated both processes at both periods with the most pronounced effect (7-fold) on invasion in late first trimester. The ET-1/ET-receptor system changes between weeks 6-9 and 10-12 in pregnancy. Our data suggest an autocrine and endocrine ET-1 effect, which is stronger in late than in early first trimester of pregnancy paralleled by different stimulatory effects on trophoblast invasion and proliferation. In general, this suggests time as an additional effector of the critical processes governing placental development in the first trimester of human pregnancy.

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Effects of adiponectin on human trophoblast invasion

Journal of Endocrinology ◽

10.1677/joe-10-0170 ◽

2010 ◽

Vol 207 (1) ◽

pp. 45-53 ◽

Cited By ~ 38

Author(s):

Delphine Benaitreau ◽

Esther Dos Santos ◽

Marie-Christine Leneveu ◽

Nadia Alfaidy ◽

Jean-Jacques Feige ◽

...

Keyword(s):

First Trimester ◽

Extravillous Trophoblast ◽

Trophoblast Invasion ◽

Placental Development ◽

Independent Manner ◽

Human Trophoblast ◽

Pathological Conditions ◽

First Trimester Of Pregnancy ◽

Insight Into

Adiponectin is an adipokine with insulin-sensitizing, anti-inflammatory, anti-atherogenic, and anti-proliferative effects. The expression of specific adiponectin receptors in the placenta and in the endometrium suggests a role for this cytokine in placental development, but this role has not yet been elucidated. The invasion of trophoblast cells during the first trimester of pregnancy being crucial to placentation process, we have studied adiponectin effects on human trophoblast invasive capacities. We found that adiponectin stimulated human trophoblast cell migration in HTR-8/SVneo cells in a dose-independent manner. In addition, adiponectin also significantly enhanced invasion of HTR-8/SVneo cells and of human extravillous trophoblast from first trimester placenta. These pro-invasive effects of adiponectin in human trophoblasts seem to be mediated in part via increased matrix metalloproteinases (MMP2 and MMP9) activities and via repression of TIMP2 mRNA expression. Our results suggest that adiponectin could be a positive regulator of the early invasion process by modulating the MMP/TIMP balance. Moreover, these results provide an insight into the role of adiponectin in pathological conditions characterized by insufficient or excessive trophoblast invasion.

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Differential expression of angiotensin II type 1 and type 2 receptors at the maternal–fetal interface: potential roles in early placental development

Reproduction ◽

10.1530/rep-10-0307 ◽

2010 ◽

Vol 140 (6) ◽

pp. 931-942 ◽

Cited By ~ 16

Author(s):

C L Tower ◽

S Lui ◽

N R Charlesworth ◽

S D Smith ◽

J D Aplin ◽

...

Keyword(s):

Angiotensin Ii ◽

Expression Patterns ◽

First Trimester ◽

Trophoblast Invasion ◽

Receptor Subtypes ◽

Ang Ii ◽

Placental Development ◽

Specific Expression ◽

Hofbauer Cells ◽

Maternal Fetal Interface

Angiotensin II (Ang II) is locally generated in the placenta and regulates syncytial transport, vascular contractility and trophoblast invasion. It acts through two receptor subtypes, AGTR1 and AGTR2 (AT1 and AT2), which typically mediate antagonising actions. The objectives of this study are to characterise the cellular distribution of AGTR1 and AGTR2 at the maternal–fetal interface and explore the effects on cytotrophoblast turnover. Low levels ofAGTR2mRNA were detected in first trimester placental homogenates using real-time PCR. Immunohistochemistry using polyclonal antibodies against AGTR1 and AGTR2 detected the receptors in first trimester placenta, decidua basalis and villous tip outgrowths in culture. Serial staining with cytokeratin-7 was used to identify extravillous trophoblasts (EVTs). AGTR1 was found in the syncytiotrophoblast microvillous membrane, in a subpopulation of villous cytotrophoblasts, and in Hofbauer cells. AGTR1 was strongly upregulated in cytotrophoblasts in cell columns and villous tip outgrowths, but was absent in interstitial and endovascular EVTs within the decidua. AGTR2 immunostaining was present in Hofbauer cells and villous cytotrophoblasts, but was absent from syncytiotrophoblast. Faint staining was detected in cell column cytotrophoblasts and villous outgrowths, but not in EVTs within the decidua. Both receptors were detected in placental homogenates by western blotting. Ang II significantly increased proliferation of cytotrophoblasts in both villous explants and villous tip outgrowths, but did not affect apoptosis. Blockade of AGTR1 and AGTR2 together abrogated this effect. This study shows specific expression patterns for AGTR1 and AGTR2 in distinct trophoblast populations at the maternal–fetal interface and suggests that Ang II plays a role in placental development and generation of EVTs.

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Expression of interleukin-6 (IL-6), signal transducer and activator of transcription-3 (STAT-3) and telomerase in choriocarcinomas

Surgical and Experimental Pathology ◽

10.1186/s42047-020-00080-1 ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Luciana Pietro ◽

Fátima Bottcher-Luiz ◽

Lício Augusto Velloso ◽

Joseane Morari ◽

Marcelo Nomura ◽

...

Keyword(s):

Cell Transformation ◽

First Trimester ◽

Bewo Cell ◽

Placental Development ◽

Trimester Abortion ◽

Bewo Cells ◽

Culture Cells ◽

Bewo Cell Line ◽

Blastocyst Implantation ◽

First Trimester Of Pregnancy

Abstract Blastocyst implantation and neoplastic invasion have some common properties related to tissue invasion, mediated by various cytokines. Aim To compare the expression of IL-6, STAT-3 and telomerase in material of abortions in the first trimester of pregnancy, at term placentas and in choriocarcinomas. Methods Immunohistochemical reactions were performed on formalin fixed and included in paraffin samples from 3 groups: abortions, normal at term placentas and choriocarcinomas. Western Blot and Real-Time PCR assays were performed on fresh material from BeWo cell line and in primary culture cells of normal placenta. Results Immunohistochemical reactions: IL-6 expression was moderate in the first trimester abortion samples and high in at term placentas and choriocarcinomas. STAT-3 was strongly positive in all groups. Telomerase expression was absent in normal at term placentas but was increased in BeWo cells. Conclusion IL-6 and STAT-3 are present in the invasion process of the normal placental development and they are maintained during the malignant transformation to choriocarcinoma. The intense telomerase expression observed in BeWo cells was strongly associated with the malignant phenotype, confirming it as a good marker for cell transformation and tumor progression.

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The Role of Kisspeptin in the Ovarian Cycle, Pregnancy, and Fertility

10.5772/intechopen.98446 ◽

2021 ◽

Author(s):

Erin Ahart ◽

Elaine Phillips ◽

Michael Wolfe ◽

Courtney Marsh

Keyword(s):

First Trimester ◽

Maternal Plasma ◽

Gonadotropin Releasing Hormone ◽

Trophoblast Invasion ◽

Diagnostic Potential ◽

Beta Hcg ◽

Hypothalamic Nuclei ◽

First Trimester Of Pregnancy ◽

Regulatory Functions

Kisspeptins are a group of neuropeptides with regulatory functions related to puberty, fertility, and reproduction. They are primarily produced by hypothalamic nuclei and are thought to regulate the activity of neurons that produce gonadotropin-releasing hormone. They are also expressed by placental syncytiotrophoblasts in developing pregnancies and are likely involved in the processes of trophoblast invasion and placentation. Similarly to beta-hCG, kisspeptins are found in maternal plasma during the first trimester of pregnancy and increase proportionately with gestational age. Because of their role in implantation, there is currently interest in the use of kisspeptins as minimally invasive biomarkers. It is suspected that maternal kisspeptin levels have diagnostic potential in identifying viable early pregnancies.

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The endothelin-1/endothelin-receptor system in human trophoblast: Changes between early and late first trimester of pregnancy

Journal of the Society for Gynecologic Investigation ◽

10.1016/s1071-5576(97)86117-5 ◽

1998 ◽

Vol 5 (1) ◽

pp. 49A-49A ◽

Cited By ~ 1

Author(s):

M CERVAR ◽

S BARTH ◽

G HUPPERTZ ◽

G DESOYE

Keyword(s):

First Trimester ◽

Endothelin Receptor ◽

Receptor System ◽

Human Trophoblast ◽

Endothelin 1 ◽

First Trimester Of Pregnancy

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Endothelial cytokines influence trophoblast invasion during first trimester of pregnancy

Placenta ◽

10.1016/j.placenta.2015.07.295 ◽

2015 ◽

Vol 36 (9) ◽

pp. A36

Author(s):

Gregor Weiss ◽

Berthold Huppertz ◽

Monika Siwetz ◽

Ingrid Lang-Olip ◽

Gerit Moser

Keyword(s):

First Trimester ◽

Trophoblast Invasion ◽

First Trimester Of Pregnancy

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304. DECIDUAL HtrA3 NEGATIVELY REGULATES TROPHOBLAST INVASION

Reproduction Fertility and Development ◽

10.1071/srb10abs304 ◽

2010 ◽

Vol 22 (9) ◽

pp. 104

Author(s):

H. Singh ◽

S. Makino ◽

Y. Endo ◽

G. Nie

Keyword(s):

Western Blotting ◽

Protease Activity ◽

Specific Inhibitor ◽

First Trimester ◽

Dominant Negative ◽

Trophoblast Invasion ◽

Wild Type ◽

Placental Development ◽

Endometrial Stromal Cells ◽

Decidual Cells

Controlled trophoblast invasion cell into the maternal decidua (interstitial invasion) is important for placental development. Abnormalities in the invasion process may lead to pregnancy complications. Decidua secrets many factors to control trophoblast invasion. Serine protease HtrA3 is highly expressed in the decidual cells in the late secretory phase of the menstrual cycle and throughout pregnancy. It is highly expressed in first trimester in most trophoblast cell types, but not in the invading interstitial trophoblast. HtrA3 and its family members are down-regulated in a number of cancers and are proposed as tumor suppressors. We hypothesized that HtrA3 is an inhibitor of trophoblast invasion. The current study aimed to investigate whether HtrA3 secreted by decidual cells regulates trophoblast invasion. Human endometrial stromal cells (HESC) were decidualised with estradial, medroxyprogesterone acetate and cyclic AMP. Real-time RT-PCR, western blotting and immunocytochemistry demonstrated that decidualisation increased HtrA3 mRNA and protein expression. HtrA3 was also detected by western blotting in the conditioned media (CM) of decidualised HESC (96h), confirming its secretory nature. For functional studies, wild type and protease inactive mutant HtrA3 were produced using wheat germ cell-free technology. The mutant has negligible protease activity and significantly inhibited the wild type protease activity, supporting its dominant-negative inhibition and utility as a specific inhibitor of the wild type protein. CM of decidualised HESC suppressed invasion of trophoblast HTR-8 cells, whereas inhibition of HtrA3 in the decidual HESC CM by exogeneous addition of HtrA3 mutant increased trophoblast HTR-8 cell invasion. These results strongly support our hypothesis that decidual HtrA3 negatively regulates trophobalst invasion.

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Endothelial dysfunction in the first trimester of pregnancy

GYNECOLOGY ◽

10.26442/20795696.2020.3.200147 ◽

2020 ◽

Vol 22 (3) ◽

pp. 59-64

Author(s):

Alexey V. Mironov ◽

Madina M. Umakhanova ◽

Alexandr V. Zhukocky

Keyword(s):

Endothelial Dysfunction ◽

Endothelial Function ◽

Pregnant Women ◽

Average Diameter ◽

First Trimester ◽

Obstetric Complications ◽

Trophoblast Invasion ◽

Vessel Lumen ◽

Apoptosis Protein ◽

First Trimester Of Pregnancy

Relevance. Endothelial pathology is an important factor in the development of obstetric complications. Endothelial dysfunction means a violation of vascular homeostasis and leads to critical changes in the microcirculatory system. These changes in early pregnancy disrupt the processes of trophoblast invasion, determining obstetric complications. Aim. To improve the diagnosis of fetoplacental system disorders by examining endothelial function in the first trimester of pregnancy. Materials and methods. 180 pregnant women in the first trimester were examined: 90 women who were diagnosed with a failed miscarriage and had an instrumental removal of the fetal egg, as well as 90 somatically healthy pregnant women who had an instrumental abortion at will. Endothelial status was diagnosed in the groups: concentrations of C-reactive protein, von Willebrand factor and apoptosis protein p53 in serum, albumin in urine were determined, and desquamated endothelial cells were counted in peripheral blood. After instrumental removal of the fetal egg in all pregnant women studied, morphometry of fetal chorion vessels was performed: the average wall thickness of the primary vessel, the average diameter of the vessel lumen, the average area of the vessel lumen, and the Kernohan index were determined. The obtained results were subjected to statistical analysis. Conclusions. The study of endothelial function in the first trimester of pregnancy can be used as a test for detecting vascular disorders in pregnant women, being an important criterion for early diagnosis of obstetric complications.

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Morphological and immunohistochemical especially of stilled pregnancy the first trimester

Journal of obstetrics and women s diseases ◽

10.17816/jowd63460-68 ◽

2014 ◽

Vol 63 (4) ◽

pp. 60-68

Author(s):

Tat’yana Georgievna Tral ◽

Gulrukhsor Khaybulloevna Tolibova

Keyword(s):

Estrogen Receptor ◽

Menstrual Cycle ◽

Histological Examination ◽

Gestational Age ◽

First Trimester ◽

Trophoblast Invasion ◽

Endometrial Stroma ◽

First Trimester Of Pregnancy ◽

Complete Transformation

Results of histological examination showed that stilled pregnancy occurs not only when the incomplete transformation of endometrial stroma, but also in terms of its full maturation regardless of hormonal support to maintain pregnancy. With increasing gestational age, regardless of hormonal support of pregnancy complete transformation of the endometrium occurs significantly more frequently. Furthermore, role hormonal drugs is not critical for the formation of endometrial glandular system. Increased expression of estrogen receptor in the glands and stroma of endometrium during pregnancy indicate the pathology of the first phase of the menstrual cycle. The reduction of the expression of KISS1 in endometrium during pregnancy was observed by the end of the first trimester of pregnancy due to the fading of the first stage of trophoblast invasion.

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