205. Fractalkine, HCC-1 and MIP-1β promote human trophoblast migration

2005 ◽  
Vol 17 (9) ◽  
pp. 78
Author(s):  
N. J. Hannan ◽  
R. L. Jones ◽  
L. A. Salamonsen
Keyword(s):  
Stromal Cells ◽  
Chemokine Receptors ◽  
First Trimester ◽  
Conditioned Media ◽  
Receptor Expression ◽  
Extravillous Trophoblast ◽  
Vitro Assay ◽  
Human Trophoblast ◽  
Decidual Cells ◽  
Trophoblast Migration

Human embryo implantation is a complex process requiring the attachment of an activated blastocyst to receptive endometrial epithelium and subsequent trophoblast invasion throughout the first trimester of pregnancy. Chemokines, including fractalkine (FKN), MCP-3, HCC-1 and MIP-1β, are produced by human endometrial epithelial and decidual cells with maximal production around the time of implantation/early pregnancy.1,2 Chemokine and receptor expression was characterized in cell types at the human maternal–trophoblast interface. Highly abundant expression of chemokine receptors CX3CR1 and CCR1 was observed in first trimester placenta and in trophoblast cells.3 We hypothesized that CX3CR1 and CCR1 ligands (FKN, MCP-3, HCC-1 and MIP-1β) produced by endometrial epithelial and decidualised stromal cells at the time of implantation promote migration of human trophoblast. We aimed to localize specific chemokine receptors in human first trimester tissue, and to determine whether trophoblast migration could be stimulated by the endometrium and by chemokines. Cellular localisation of specific receptors was assessed by immunohistochemistry in human first trimester implantation sites. Using an in vitro assay, trophoblast migration was assessed in response to human endometrial epithelial (HEEC) and decidualised stromal cells (DESC) (serum-free) conditioned medium and to recombinant human FKN, MCP-3, HCC-1 and MIP-1β. CX3CR1 and CCR1 protein was localised to the vascular extravillous trophoblast (EVTs), but not to the invading interstitial EVTs, with weak staining on the syncytium. Significant migration of cells occurred in response to conditioned media from HEEC and DESC. FKN, MIP-1β and HCC-1, but not MCP-3 also promoted significant trophoblast migration. Neutralizing antibodies for FKN and MIP-1β but not MCP-3 significantly reduced migration to conditioned media, indicating that at least these two chemokines contributed to the effects. These data support a role for endometrial derived chemokines in promoting human trophoblast migration. (1)Jones et al. (2004). JCEM 89(12), 6155–6167.(2)Hannan et al. (2004). Reprod. Fert. Devel. 16(Suppl.), A225, p. 78.(3)Hannan et al. (2004). JCEM 89(12), 6119–6129.

108. FUNCTIONAL ROLE OF HtrA3 IN TROPHOBLAST CELL INVASION DURING HUMAN PLACENTAL DEVELOPMENT

2009 ◽  
Vol 21 (9) ◽  
pp. 27
Author(s):  
H. Singh ◽  
G. Nie
Keyword(s):  
Cell Invasion ◽  
Stromal Cells ◽  
Functional Role ◽  
First Trimester ◽  
Trophoblast Cell ◽  
Extravillous Trophoblast ◽  
Placental Development ◽  
Decidual Cells

Controlled invasion of extravillous trophoblast (EVT) through the maternal decidua is important for placental development and function. 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 and is down-regulated in invading EVTs, while up-regulation of decidual HtrA3 controls the process. The current study investigated HtrA3 expression in human endometrial stromal cells (HESC) during decidualization in vitro and whether HtrA3 inhibits EVT cell invasion. Stromal cells isolated from human endometrium were decidualized in vitro with estrogen, progesterone and cAMP. Quantitative RT-PCR and western showed HtrA3 mRNA and protein expression was significantly increased in decidualized HESC compared to controls. Indirect immunofluorescence showed homogeneous pattern and increase in intensity of HtrA3 staining in decidualized HESC compared to non-decidualized cells. HTR-8 cells derived from first trimester of pregnancy EVT showed higher levels of HtrA3 mRNA expression compared to other human choriocarcinoma cell lines (AC-1M88, AC-1M32, JEG-3 and BeWo). Both intracellular and extracellular HtrA3 staining was observed in HTR8 cells. Functional role of HtrA3 in cell invasion was determined in HTR-8 cells using an in vitro invasion assay. Exogenous addition of mutant HtrA3 (inhibitor) resulted in a significant increase in HTR-8 cells invading through matrigel coated membrane compared with controls. TGFβ-1 (as positive control) completely inhibited invasion of HTR-8 cells. HtrA3 is tightly regulated during decidualization of HESC in vitro. Inhibition of HtrA3 activity in trophoblastic HTR-8 cells increased invasiveness supporting its functional role during placental development.

scholarly journals Ghrelin Is Involved in the Decidualization of Human Endometrial Stromal Cells

2003 ◽  
Vol 88 (5) ◽  
pp. 2335-2340 ◽  
Author(s):  
Keisuke Tanaka ◽  
Hiroyuki Minoura ◽  
Tetsuya Isobe ◽  
Hitoshi Yonaha ◽  
Hiroaki Kawato ◽  
...  
Keyword(s):  
Menstrual Cycle ◽  
Early Pregnancy ◽  
Stromal Cells ◽  
Immunohistochemical Analysis ◽  
First Trimester ◽  
Extravillous Trophoblast ◽  
Endometrial Stromal Cells ◽  
Decidual Cells ◽  
Normal Menstrual Cycle

Successful implantation involves a complex interaction between the endometrium and the embryo. It is well known that several neuropeptides are expressed in the endometrium and placenta during embryonal implantation, suggesting an important role as chemical mediators of the feto-maternal relationship. Ghrelin has recently been identified as the endogenous ligand for the GH secretagogue receptor. Ghrelin is a peptide hormone with many physiological functions, and its expression in the human placenta has been reported. To investigate the involvement of ghrelin in embryonal implantation, we assessed the spatio-temporal expression pattern of ghrelin and its receptor in the human endometrium and placenta through the normal menstrual cycle and in early pregnancy. We also examined the effect of ghrelin on the decidualization of endometrial stromal cells (ESC). Weak expression of ghrelin mRNA was detected in the nonpregnant endometrium, and it was dramatically increased in the decidualized endometrium. A GH secretagogue receptor mRNA was detected in the endometrium throughout the normal menstrual cycle and in early pregnancy, but not in the first trimester placenta. Immunohistochemical analysis using an antighrelin antibody revealed strong signals in decidual cells and extravillous trophoblast cells. Coculture with first trimester placenta up-regulated ghrelin mRNA expression by primary cultured ESC, although sex steroids and 8-bromo-cAMP had no effect. In addition, ghrelin enhanced the decidualization of ESC induced by 8-bromo-cAMP (8-Br-cAMP) in vitro. Thus, ghrelin is a novel paracrine/autocrine factor that is involved in cross-talk between the endometrium and embryo during embryonal implantation.

213. Chemokines: key players at the maternal - fetal interface

2008 ◽  
Vol 20 (9) ◽  
pp. 13
Author(s):  
N. J. Hannan ◽  
L. A. Salamonsen
Keyword(s):  
Extracellular Matrix ◽  
Real Time ◽  
Extracellular Matrix Protein ◽  
Leukocyte Trafficking ◽  
Trophoblast Cells ◽  
Rt Pcr ◽  
Human Trophoblast ◽  
Decidual Cells ◽  
Trophoblast Migration ◽  
Maternal Fetal Interface

Establishment of pregnancy requires extensive communication at the maternal-fetal interface and involves a plethora of locally acting molecules, including the chemokines. Chemokines are multifunctional molecules initially described for roles in leukocyte trafficking, but since found to participate in many other processes such as differentiation and directed migration. Previously we have shown that the chemokines, CX3CL1 and CCL14, are abundant in human endometrial vasculature, leukocytes, epithelial and decidual cells at the time of implantation and that their receptors, CX3CR1 and CCR1, are present on invading human trophoblast. CX3CL1 and CCL14 directly promote human trophoblast migration. We hypothesised that these endometrial chemokines promote trophoblast migration by regulating adhesion molecules and extracellular matrix (ECM) components on the trophoblast, similar to mechanisms used in leukocyte trafficking. Trophoblast cells (AC1M-88) used previously, showed a marked increase in adhesion to fibronectin following treatment with CX3CL1 and CCL14. Alterations in trophoblast adhesion associated and ECM genes following chemokine stimulation were examined using pathway specific oligo-arrays and quantitative real-time RT–PCR. Over 30 transcripts were affected by CX3CL1 treatment and 15 were regulated by CCL14 treatment. Real-time RT–PCR confirmed significant changes in the mRNA transcripts of α-catenin (CTNNA1), extracellular matrix protein-1 (ECM1), osteopontin (SPP1), integrin α6 (ITGA6), matrix metalloproteinase-12 (MMP12) and integrin β5 (ITGB5) following chemokine treatment. Several of these molecules have previously been implicated in implantation. Immunohistochemistry confirmed the presence of integrin α6, SPP1 and ECM1 protein in first trimester human implantation sites. The temporal and spatial expression of chemokines, their receptors and adhesion related molecules at the maternal-fetal interface emphasises an important role in the controlled directional migration of trophoblast through the maternal decidua. For the first time this study demonstrates direct effects of CX3CL1 and CCL14 on trophoblast adhesion and ECM molecules suggesting mechanisms by which trophoblast cells migrate during early pregnancy.

scholarly journals Human endogenous retrovirus-W envelope (syncytin) is expressed in both villous and extravillous trophoblast populations

2006 ◽  
Vol 87 (7) ◽  
pp. 2067-2071 ◽  
Author(s):  
A. Muir ◽  
A. M. L. Lever ◽  
A. Moffett
Keyword(s):  
Cell Lines ◽  
First Trimester ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Extravillous Trophoblast ◽  
Human Endogenous Retrovirus ◽  
Human Trophoblast ◽  
Human Endogenous Retroviruses ◽  
Normal Tissues ◽  
Villous Trophoblast

The placenta is unique amongst normal tissues in transcribing numerous different human endogenous retroviruses at high levels. In this study, RT-PCR and immunohistochemistry were used to investigate the expression of syncytin in human trophoblast. Syncytin transcripts were found in first-trimester trophoblast cells with both villous and extravillous phenotypes and also in the JAR and JEG-3 choriocarcinoma cell lines. Syncytin protein was detected in villous trophoblast and in all extravillous trophoblast subpopulations of first- and second-trimester placental tissues. It was also present in ectopic trophoblast from tubal implantations. This study confirms that syncytin is expressed widely by a variety of normal human trophoblast populations, as well as choriocarcinoma cell lines.

scholarly journals Opposite Effects of Transforming Growth Factor-β Activation and Rho-Associated Kinase Inhibition on Human Trophoblast Migration in a Reconstituted Placental-Endometrial Coculture System

Endocrinology ◽  
2008 ◽  
Vol 149 (9) ◽  
pp. 4475-4485 ◽  
Author(s):  
Patrick Fafet ◽  
Cosette Rebouissou ◽  
Thierry Maudelonde ◽  
Marie-Luce Vignais
Keyword(s):  
Transforming Growth Factor ◽  
Cell Layer ◽  
Chorionic Villus ◽  
Transforming Growth Factor Β ◽  
Time Lapse ◽  
First Trimester ◽  
Trophoblast Invasion ◽  
Endometrial Cell ◽  
Human Trophoblast ◽  
Trophoblast Migration

Placental implantation involves highly regulated trophoblast invasion of the endometrial stroma. TGFβ is a known regulator of this process. This study examines the effect of TGFβ on extravillous cytotrophoblastic cell (EVCT) migration in cocultures of first-trimester human chorionic villus explants and primary human endometrial fibroblasts. Migration of EVCTs was followed by phase-contrast time-lapse microscopy and was shown to highly depend on the endometrial fibroblast matrix. Interstitial EVCT invasion was also analyzed by confocal microscopy of fluorescently prelabeled trophoblasts and endometrial fibroblasts. As expected, addition of TGFβ led to inhibition of EVCT invasion of the endometrial cell layer. This inhibition was characterized by formation of compact EVCT stacks at migration fronts and displacement of endometrial fibroblasts. We tested the role of the RhoA/Rho-associated kinase (ROCK) pathway, a TGFβ-dependent pathway known to regulate cell migration. Interestingly, blocking ROCK with the chemical inhibitor Y27632 had an effect opposite to TGFβ activation because it promoted superficial EVCT migration on the endometrial cell layer. These data suggest a role for ROCK in the TGFβ-dependent control of trophoblast migration. Furthermore, they indicate that even though ROCK signaling plays a role in human trophoblast cell invasion, EVCT migration can still occur in the absence of ROCK activity.

scholarly journals Effects of adiponectin on human trophoblast invasion

2010 ◽  
Vol 207 (1) ◽  
pp. 45-53 ◽  
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.

scholarly journals BMP6 Mediates BMP2-Increased Human Trophoblast Invasion

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A747-A747
Author(s):  
Jianye Deng ◽  
Yan Li
Keyword(s):  
Molecular Mechanisms ◽  
First Trimester ◽  
Bone Morphogenetic Protein 2 ◽  
Extravillous Trophoblast ◽  
Trophoblast Invasion ◽  
Mrna Levels ◽  
Ongoing Research ◽  
Human Trophoblast ◽  
Protein Levels ◽  
Regulatory Effects

Abstract TGF-β superfamily proteins play divergent roles in regulating human extravillous trophoblast (EVT) invasion and their coordinated effects are essential for adequate placentation during pregnancy 1. Bone morphogenetic protein 2 (BMP2), which belongs to the BMP subfamily of TGF-β superfamily, has been shown to promote human EVT invasion and the acquisition of endothelial-like phenotype 2,3. It has been reported that BMP2 promotes EVT invasion by up-regulating Activin A, a growth factor which also belongs to TGF-β superfamily. However, whether BMP6 mediates the pro-invasive effect of BMP2 has yet to be determined. Herein, we firstly treated immortalized trophoblast cells (HTR8/SVneo) with recombinant BMP2 protein for 6 and 24 hrs, and our bulk-RNA sequencing results demonstrated significantly increased BMP6 mRNA levels after BMP2 treatment. Furthermore, we confirmed the up-regulatory effects of BMP2 on BMP6 mRNA and protein levels in both HTR8/SVneo and primary EVTs isolated from first-trimester villi. Notably, siRNA-mediated down-regulation of BMP6 significantly attenuated both basal and BMP2-induced cell invasion in HTR8/SVneo cells as measured by Matrigel-coated transwell invasion assay. In summary, our results firstly demonstrated the up-regulatory effect of BMP2 on BMP6 expression in human trophoblasts and identified the mediation role of BMP6 in BMP2-promoted EVT invasion, suggesting the interplay between BMP subfamily members during EVT invasion regulation. Our ongoing research focusing the underlying molecular mechanisms and signaling pathways could further benefit the advancement of diagnostic and therapeutic strategies for EVT invasion dysregulation-related pregnancy disorders, e.g., pre-eclampsia. Reference: (1) Li Yan et al., Trends Endocrinol Metab 2021 18: S1043-2760(20)30266-6. (2) Hong-Jin Zhao et al., FASEB J 2020;34(2):3151-3164. (3) Hong-Jin Zhao et al., Cell Death Dis 2018;9(2):174.

Regulation of human trophoblast migration and invasiveness

2002 ◽  
Vol 80 (2) ◽  
pp. 116-124 ◽  
Author(s):  
Chandan Chakraborty ◽  
Louise M Gleeson ◽  
Timothy McKinnon ◽  
Peeyush K Lala
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Plasminogen Activator ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Extravillous Trophoblast ◽  
Type I ◽  
Human Trophoblast ◽  
Trophoblast Migration

The human placenta is an invasive structure in which highly proliferative, migratory, and invasive extravillous trophoblast (EVT) cells migrate and invade the uterus and its vasculature. Using in vitro propagated normal first-trimester EVT cells and immortalized EVT cells, which share all of the phenotypic and functional characteristics of the normal EVT cells, it has been shown that migration/invasion of human EVT cells is stringently regulated by many growth factors, their binding proteins, extracellular matrix (ECM) components, and some adhesion molecules in an autocrine/paracrine manner at the fetal–maternal interface in human pregnancy. Transforming growth factor β (TGF-β), decorin (a proteoglycan in the ECM), and melanoma cell adhesion molecule (Mel-CAM) inhibit, and insulin-like growth factor II (IGF-II), IGF-binding protein 1 (IGFBP-1), and endothelin 1 (ET-1) stimulate EVT cell migration/invasion. Inhibition of EVT cell migration by TGF-β has been suggested to be due to upregulation of integrins, which make the cells more adhesive to the ECM. Its antiinvasive action is due to an upregulation of tissue inhibitor of matrix metalloprotease 1 (TIMP-1) and plasminogen activator inhibitor (PAI-1) and a downregulation of urokinase-type plasminogen activator (uPA). Molecular mechanisms of inhibition of migration/invasion of EVT cells by decorin and Mel-CAM remain to be identified. IGF-II action has been shown to be mediated by IGF type I receptors (IGF-RII) independently of IGF type I receptors (IGF-RI) and IGFBPs. This action of IGF-II appears to involve inhibitory G proteins and phosphorylation of mitogen-activated protein kinase (MAPK) (extracellular signal-regulated protein kinases 1 and 2 (ERK-1 and ERK-2)). IGFBP-1 stimulation of EVT cell migration appears to occur by binding its Arg-Gly-Asp (RGD) domain to α5β1 integrin, leading to phosphorylation of focal adhesion kinase (FAK) and MAPK (ERK-1 and ERK-2). These studies may improve our understanding of diseases related to abnormal placentation, viz. hypoinvasiveness in preeclampsia and hyperinvasiveness in trophoblastic neoplasms.Key words: trophoblast, migration, integrin, IGF-RII, IGFBP-1.

scholarly journals Small Guanosine Triphospatase RhoA and Rho-Associated Kinase as Regulators of Trophoblast Migration

2002 ◽  
Vol 87 (12) ◽  
pp. 5808-5816 ◽  
Author(s):  
Shigetatsu Shiokawa ◽  
Mitsutoshi Iwashita ◽  
Yoshihiro Akimoto ◽  
Shinya Nagamatsu ◽  
Ken Sakai ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Stress Fibers ◽  
Extravillous Trophoblast ◽  
Dependent Manner ◽  
Focal Contact ◽  
Trophoblast Cells ◽  
Human Trophoblast ◽  
Trophoblast Migration ◽  
Human Trophoblast Cells ◽  
Actin Stress Fibers

Abstract The small guanosine triphosphatase Rho controls cell adhesion and motility through reorganization of the actin cyto-skeleton and regulation of actomyosin contractility. Among the putative target molecules of Rho, a Rho-associated coiled coil-forming protein kinase (ROCK) is thought to participate in Rho-mediated cell adhesion and motility. In the present study, we explored the expression and function of RhoA and ROCK in human trophoblast cells. The colocalization of RhoA, cytokeratin 8/18, and cytokeratin 7 in some cells located in the decidual stromal region indicated that extravillous trophoblast cells expressed RhoA. In double staining for RhoA and ROCK in human chorionic villi, RhoA staining was strongly positive in the cytoplasm of cytotrophoblasts, whereas ROCK stained in the cytoplasm of cytotrophoblasts and syncytiotrophoblasts. Both RhoA and ROCK were stained in cytoplasma of cultured human cytotrophoblast. Cultured human trophoblast cells contained actin stress fibers that were lost after treatment with C3, an exoenzyme produced by Clostridium botulinum. Y-27632, a selective ROCK inhibitor, suppressed RhoA-induced formation of actin stress fibers and formation of focal contact in trophoblast cells. The trophoblast reacquired actin stress fibers and focal contact after withdrawal of Y-27632. Cultured human cytotrophoblast cells from 7–9 wk of gestation migrated into a fibronectin-coated membrane. Both C3 exoenzyme and Y-27632 inhibited cytotrophoblast migration in a dose-dependent manner. In conclusion, cyto-trophoblasts express RhoA and ROCK in their cytoplasm, and RhoA-ROCK is involved in their assembly of actin stress fibers. Suppression of RhoA-ROCK reduces trophoblast migration. These findings suggest that RhoA-ROCK signaling is a key regulator of trophoblast cell migration.

scholarly journals Roles of Rho Guanosine 5′-Triphosphatase A, Rho Kinases, and Extracellular Signal Regulated Kinase (1/2) in Prostaglandin E2-Mediated Migration of First-Trimester Human Extravillous Trophoblast

Endocrinology ◽  
2007 ◽  
Vol 149 (3) ◽  
pp. 1243-1251 ◽  
Author(s):  
Catalin Nicola ◽  
Andrei Chirpac ◽  
Peeyush K. Lala ◽  
Chandan Chakraborty
Keyword(s):  
Chorionic Villus ◽  
Rho Kinase ◽  
First Trimester ◽  
The Other ◽  
Extravillous Trophoblast ◽  
Small Interfering Rnas ◽  
Rock Inhibitor ◽  
Trophoblast Migration ◽  
Stimulation Of

Prostaglandin (PG) E2 may regulate invasiveness of human placenta because we previously reported stimulation of migration of placental trophoblasts by PGE2 acting through PGE receptor (EP)-1 and activating calpain. RhoA GTPase and its important effector Rho kinase (ROCK) have also been previously shown to regulate trophoblast migration. Using immortalized HTR-8/SVneo trophoblast cells and first-trimester human chorionic villus explant cultures on matrigel, we further examined the role of RhoA/ROCK and MAPK (ERK1/2) pathways on PGE2-mediated stimulation of trophoblast migration. Migration of cytotrophoblasts was shown to be inhibited by treatment of the trophoblast cell line and chorionic villus explants with either cell-permeable C3 transferase or selective RhoA small interfering RNA. These inhibitions were significantly mitigated by the addition of PGE2, an EP1/EP3 agonist or an EP3/EP4 agonist, suggesting that RhoA plays an important role in trophoblast migration but may not be obligatory for PGE2 action. Treatment of HTR-8/SVneo cells with nonselective ROCK inhibitor Y27632 or ROCK small interfering RNAs inhibited migration of these cells, which could not be rescued with PGE2 or the other two EP agonists, suggesting the obligatory role of ROCK in PGE2-induced migratory response. Furthermore, U0126, an inhibitor of MAPK kinases MEK1 and MEK2, abrogated PGE2-induced migration of trophoblasts, and PGE2 or the other two EP agonists stimulated ERK1/2 activation in trophoblasts, which was not abrogated by pretreatment with C3 transferase, indicating that ERK signaling pathway is an efficient alternate pathway for RhoA in PGE2-mediated migration of trophoblasts. These results suggest that ROCK and ERK1/2 play more important roles than RhoA in PGE2-mediated migration stimulation of first-trimester trophoblasts.

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