Pathogenesis Of Fetal Growth Restriction Research Articles

Genome-Wide Analysis in the Study of the Fetal Growth Restriction Pathogenetics

Fetal growth restriction is a complication of pregnancy that defined as the inability of the fetus to realize its genetically determined growth potential. Despite the high social and medical significance of this problem the exact pathogenesis of fetal growth restriction is not known by now. Therefore, the analysis of the molecular genetics mechanisms of this pathology within the framework of approaches using modern high-performance technologies of next generation sequencing is of undoubted interest. In this review we focused on the analysis of data obtained in studies of the fetal growth restriction genetics component. The authors of these researches used next generation sequencing technologies and carried out whole transcriptome profiling. The results of the genes expression genome-wide analysis in placental tissue allow us to identify 1430 differentially expressed genes between fetal growth restriction and normal pregnancy, of which only 1% were found in at least two studies. These differentially expressed genes are involved in the Wnt/β-catenin signaling pathway that plays an important role in cell migration, neural pattern formation and organogenesis during embryonic development. Common genes are associated with both obstetric and gynecological diseases, as well as with various somatic conditions from the groups of neurodegenerative, cardiovascular diseases and mental disorders, which probably reflects their involvement in the development of postnatal consequences of fetal growth restriction. The results of our work don‘t point only to potential molecular mechanisms and key genes underlying fetal growth restriction, but also indicate the important role of gene-gene communications in this pathology implementation: about 30% of all identified differentially expressed genes products interact with each other within the same gene network. In general, genome-wide RNA sequencing combined with the analysis of protein-protein interactions represents a promising direction in research on the development and functioning of the placenta, as well as the identification of placental insufficiency diseases genetics mechanisms, including fetal growth restriction.

New Marker in the Umbilical Cord Blood of Fetuses with Fetal Growth Restriction: Serum Sortilin-1 Level

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.

Trophoblast fusion in fetal growth restriction is inhibited by CTGF in a cell-cycle-dependent manner.

Fetal growth restriction (FGR) is a relatively common complication of pregnancy, and insufficient syncytialization in the placenta may play an important role in the pathogenesis of FGR. However, the mechanism of impaired formation of the syncytiotrophoblast layer in FGR patients requires further exploration. In the present study, we demonstrated that the level of syncytialization was decreased in FGR patient placentas, while the expression of connective tissue growth factor (CTGF) was significantly upregulated. CTGF was found to inhibit trophoblast fusion via regulating cell cycle progress of BeWo cells. Furthermore, we found that CTGF negatively regulates cell cycle arrest in a p21-dependent manner as overexpression of p21 could rescue the impaired syncytialization induced by CTGF-overexpression. Besides, we also identified that CTGF inhibits the expression of p21 through ITGB4/PI3K/AKT signaling pathway. Our study provided a new insight for elucidating the pathogenic mechanism of FGR and a novel idea for the clinical therapy of FGR.

AT-rich interactive domain-containing protein 1A (ARID1A) expression in placentas with late fetal growth restriction

BACKGROUND: Fetal growth restriction, which is considered as a multifactorial pathology, is a critical problem in obstetrics. The role of mitochondrial dysfunction in the pathogenesis of fetal growth restriction is not yet clear. However, it is known that it leads to oxidative stress, damage to cells and tissues, and dysfunction of key mechanisms for maintaining energy balance, the outcome of which may be the development of placental insufficiency. It is likely that AT-rich interactive domain-containing protein 1A (ARID1A) is involved in the development and function of the human placenta and may be an important marker in the development of fetal growth restriction. AIM: The aim of this study was to evaluate ARID1A protein expression in the placental villous tree in late fetal growth restriction. MATERIALS AND METHODS: This study included 50 placentas from children born at full-term gestation (37–40 weeks). The main study group consisted of placentas with late fetal growth restriction and without major extragenital pathology (n = 35). The control group comprised 15 placentas without fetal growth restriction (n = 15). Histological (n = 50) and immunohistochemical examinations of placentas (15 placentas in the main group and 10 placentas in the control group) using primary monoclonal antibodies to ARID1A were performed. RESULTS: In the study group with fetal growth restriction, chronic placental insufficiency was verified in all cases, dissociated chronic placental insufficiency (25 cases; 71.4%) being predominant, of which 23 cases (92%) were compensated, including 16 cases (69.6%) with moderate circulatory disorders. Hypoplastic chronic placental insufficiency was diagnosed in ten cases (28.6%) and was subcompensated with the presence of pronounced circulatory disorders. In the arteries of the stem villi, the ARID1A protein expression area did not differ between the study groups (p = 0.096), while in the veins in the stem villi with fetal growth restriction, we verified a decrease compared to control (p = 0.05). In the vascular bed of the villi with subcompensated dissociated chronic placental insufficiency, ARID1A protein expression was higher compared to hypoplastic chronic placental insufficiency (p = 0.041). CONCLUSIONS: Chronic placental insufficiency combined with fetal growth restriction is a serious complication of pregnancy with the development of structural and functional abnormalities and dysregulation of placental mechanisms. The ARIDA1A protein expression data obtained, depending on the degree of compensation for chronic placental insufficiency, may indicate the activation of compensatory metabolic mechanisms to maintain the functional activity of the placenta and preserve the viability of the fetus.

Decidual macrophages and Hofbauer cells in fetal growth restriction.

Placental macrophages, which include maternal decidual macrophages and fetal Hofbauer cells, display a high degree of phenotypical and functional plasticity. This provides these macrophages with a key role in immunologically driven events in pregnancy like host defense, establishing and maintaining maternal-fetal tolerance. Moreover, placental macrophages have an important role in placental development, including implantation of the conceptus and remodeling of the intrauterine vasculature. To facilitate these processes, it is crucial that placental macrophages adapt accordingly to the needs of each phase of pregnancy. Dysregulated functionalities of placental macrophages are related to placental malfunctioning and have been associated with several adverse pregnancy outcomes. Although fetal growth restriction is specifically associated with placental insufficiency, knowledge on the role of macrophages in fetal growth restriction remains limited. This review provides an overview of the distinct functionalities of decidual macrophages and Hofbauer cells in each trimester of a healthy pregnancy and aims to elucidate the mechanisms by which placental macrophages could be involved in the pathogenesis of fetal growth restriction. Additionally, potential immune targeted therapies for fetal growth restriction are discussed.

Integrative profiling of extrachromosomal circular DNA in placenta and maternal plasma provides insights into the biology of fetal growth restriction and reveals potential biomarkers.

Introduction: Fetal growth restriction (FGR) is a placenta-mediated pregnancy complication that predisposes fetuses to perinatal complications. Maternal plasma cell-free DNA harbors DNA originating from placental trophoblasts, which is promising for the prenatal diagnosis and prediction of pregnancy complications. Extrachromosomal circular DNA (eccDNA) is emerging as an ideal biomarker and target for several diseases. Methods: We utilized eccDNA sequencing and bioinformatic pipeline to investigate the characteristics and associations of eccDNA in placenta and maternal plasma, the role of placental eccDNA in the pathogenesis of FGR, and potential plasma eccDNA biomarkers of FGR. Results: Using our bioinformatics pipelines, we identified multi-chromosomal-fragment and single-fragment eccDNA in placenta, but almost exclusively single-fragment eccDNA in maternal plasma. Relative to that in plasma, eccDNA in placenta was larger and substantially more abundant in exons, untranslated regions, promoters, repetitive elements [short interspersed nuclear elements (SINEs)/Alu, SINEs/mammalian-wide interspersed repeats, long terminal repeats/endogenous retrovirus-like elements, and single recognition particle RNA], and transcription factor binding motifs. Placental multi-chromosomal-fragment eccDNA was enriched in confident enhancer regions predicted to pertain to genes in apoptosis, energy, cell growth, and autophagy pathways. Placental eccDNA-associated genes whose abundance differed between the FGR and control groups were associated with immunity-related gene ontology (GO) terms. The combined analysis of plasma and placental eccDNA-associated genes in the FGR and control groups led to the identification of potential biomarkers that were assigned to the GO terms of the epigenetic regulation of gene expression and nutrient-related processes, respectively. Conclusion: Together, our results highlight links between placenta functions and multi-chromosomal-fragment and single-fragment eccDNA. The integrative analysis of placental and plasma eccDNA confirmed the potential of these molecules as disease-specific biomarkers of FGR.

The Gut Microbiota of Pregnant Rats Alleviates Fetal Growth Restriction by Inhibiting the TLR9/MyD88 Pathway.

Fetal growth restriction (FGR) is a prevalent obstetric condition. This study aimed to investigate the role of Toll-like receptor 9 (TLR9) in regulating the inflammatory response and gut microbiota structure in FGR. An FGR animal model was established in rats, and ODN1668 and hydroxychloroquine (HCQ) were administered. Changes in gut microbiota structure were assessed using 16S rRNA sequencing, and fecal microbiota transplantation (FMT) was conducted. HTR-8/Svneo cells were treated with ODN1668 and HCQ to evaluate cell growth. Histopathological analysis was performed, and relative factor levels were measured. The results showed that FGR rats exhibited elevated levels of TLR9 and myeloid differentiating primary response gene 88 (MyD88). In vitro experiments demonstrated that TLR9 inhibited trophoblast cell proliferation and invasion. TLR9 upregulated lipopolysaccharide (LPS), LPS-binding protein (LBP), interleukin (IL)-1β and tumor necrosis factor (TNF)-α while downregulating IL-10. TLR9 activated the TARF3-TBK1-IRF3 signaling pathway. In vivo experiments showed HCQ reduced inflammation in FGR rats, and the relative cytokine expression followed a similar trend to that observed in vitro. TLR9 stimulated neutrophil activation. HCQ in FGR rats resulted in changes in the abundance of Eubacterium_coprostanoligenes_group at the family level and the abundance of Eubacterium_coprostanoligenes_group and Bacteroides at the genus level. TLR9 and associated inflammatory factors were correlated with Bacteroides, Prevotella, Streptococcus, and Prevotellaceae_Ga6A1_group. FMT from FGR rats interfered with the therapeutic effects of HCQ. In conclusion, our findings suggest that TLR9 regulates the inflammatory response and gut microbiota structure in FGR, providing new insights into the pathogenesis of FGR and suggesting potential therapeutic interventions.

Advances in Maternal–Fetal Imaging

Advances in Maternal–Fetal Imaging

A Novel Mouse Model to Examine the Double-Burden of Ambient Heat and Micronutrient Insufficiency on Fetal Growth

ObjectivesUndernutrition and malnutrition in women of childbearing age are associated with increased risk of fetal growth restriction and poor infant development. Climate change, specifically the rise in ambient temperature, is thought to exacerbate the effects of malnutrition. However, few mechanistic models exist to examine the interactions between maternal nutritional status and ambient temperature on fetal growth. MethodsFemale C57BL6/J mice (8 wk old, n = 6–8/group) were given ad libitum access to either AIN-93G (CON) or a modified AIN-93 diets containing 70% mineral, micronutrient, and vitamin mix (70MMV) for 4 weeks. The 70MMV diet is not designed to cause nutritional deficiency, but rather a lower nutritional plane. Plug positive females were housed at either 22⁰C or 33⁰C in an environmental chamber for the duration of pregnancy, while remaining on their respective diets. Body weights and food intake were assessed weekly. Placenta tissue as well as fetal, placental, and liver weights were collected at dpc 17.5. ER stress related gene targets in the placenta were assessed by RT-qPCR. ResultsBody weight gains over pregnancy were significantly reduced in animals fed 70MMV compared to CON diet. There was no change in liver to body weight ratios across groups, however there was a slight reduction in liver to body ratio in the 33⁰C compared to 22⁰C group on CON diet. Placental weights were significantly reduced in 33⁰C group, with a more severe reduction in the 70MMV + 33⁰C group. Notably, fetal weights of dams exposed to both 33⁰C and 70 MMV diet showed significant reductions in fetal weights. Two-way ANOVA for fetal weights showed a significant diet and temperature interaction. Pairwise comparisons showed no difference between temperatures on CON diet, but significantly lower fetal weights in the 70MMV + 33⁰C relative to 70MMV + 22⁰C. ConclusionsOur results point to an interaction between modest heat and micronutrient insufficiency in the pathogenesis of fetal growth restriction, highlighting the emerging nexus of maternal nutrition and heat stress typically seen in resource-restrained settings. Funding SourcesCU-Department of Pediatrics and Anschutz Health and Wellness Center.

The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction.

Fetal growth restriction (FGR) is commonly associated with placental insufficiency and inflammation. Nonetheless, the role played by inflammasomes in the pathogenesis of FGR is poorly understood. We hypothesised that placental inflammasomes are differentially expressed and contribute to the aberrant trophoblast function. Inflammasome gene expression profiles were characterised by real-time PCR on human placental tissues collected from third trimester FGR and gestation-matched control pregnancies (n = 25/group). The functional significance of a candidate inflammasome was then investigated using lipopolysaccharide (LPS)-induced models of inflammation in human trophoblast organoids, BeWo cells in vitro, and a murine model of FGR in vivo. Placental mRNA expression of NLRP3, caspases 1, 3, and 8, and interleukin 6 increased (>2-fold), while that of the anti-inflammatory cytokine, IL-10, decreased (<2-fold) in FGR compared with control pregnancies. LPS treatment increased NLRP3 and caspase-1 expression (>2-fold) in trophoblast organoids and BeWo cell cultures in vitro, and in the spongiotrophoblast and labyrinth in the murine model of FGR. However, the LPS-induced rise in NLRP3 was attenuated by its siRNA-induced down-regulation in BeWo cell cultures, which correlated with reduced activity of the apoptotic markers, caspase-3 and 8, compared to the control siRNA-treated cells. Our findings support the role of the NLRP3 inflammasome in the inflammation-induced aberrant trophoblast function, which may contribute to FGR.

Mitochondrial dysfunction-induced high hCG associated with development of fetal growth restriction and pre-eclampsia with fetal growth restriction

Fetal growth restriction (FGR) and pre-eclampsia with fetal growth restriction (PE/FGR) are high-risk perinatal diseases that may involve high levels of human chorionic gonadotropin (hCG) and mitochondrial dysfunction. However, little is known about how these factors affect placental function. We investigated how mitochondrial dysfunction and high hCG expression affected placental function in unexplained FGR and PE/FGR. We observed elevated expression of hCGβ and growth differentiation factor 15 mRNA and protein levels in the placenta with both diseases. Likewise, antiangiogenic factors, such as Ang2, IP10, sFlt1, IL8, IL1B, and TNFα, were also upregulated at the mRNA level. In addition, the expression of COXI and COXII which encoded by mitochondrial DNA were significantly decreased in both diseases, suggesting that mitochondrial translation was impaired. Treatment with hCG increased Ang2, IP10, IL8, and TNFα mRNA levels in a dose-dependent manner via the p38 and JNK pathways. Mitochondrial translation inhibitors increased hCGβ expression through stabilization of HIF1α, and increased IL8 and TNFα mRNA expression. These results revealed that high expression of hCG due to mitochondrial translational dysfunction plays an important role in the pathogenesis of FGR and PE/FGR.

Современные представления о патогенезе задержки роста плода

Современные представления о патогенезе задержки роста плода

Galectin-1 expression in the serum and placenta of pregnant women with fetal growth restriction and its significance

BackgroundThis study aims to investigate galectin-1 (Gal-1) expression in the serum and placenta of pregnant women with fetal growth restriction (FGR) and its significance.MethodsThirty-one pregnant women with single-birth FGR but without comorbidities, eight pregnant women with FGR and preeclampsia (PE), and eight pregnant women with FGR and gestational diabetes mellitus (GDM) were enrolled as the study group, while 20 pregnant women with normal singleton pregnancy in the same period were enrolled as the control group. The serum Gal-1 level was detected using an enzyme-linked immunosorbent assay (ELISA), and Gal-1 expression in the placenta was detected by western blot.ResultsThe results revealed that, compared with the control group, the serum Gal-1 level decreased in the women with FGR without comorbidities, and the difference was statistically significant (P < 0.001). Compared with the control group, the difference in serum Gal-1 expression in the FGR-PE group was not statistically significant (P = 0.29). The peripheral serum Gal-1 level decreased in the FGR-GDM group compared with the control group, and the difference was statistically significant (P < 0.001). The serum Gal-1 level was positively correlated with birth weight (r2 = 0.172, P < 0.01). Compared with the control group, the Gal-1 expression level decreased in the placenta of the pregnant women with FGR without comorbidities (P < 0.05).ConclusionsGal-1 exhibits low expression in the serum and placenta of pregnant women with FGR. In addition, Gal-1 may be involved in the pathogenesis of FGR and could represent a new diagnostic marker of the disease.

Phosphorylation of Yes-associated protein impairs trophoblast invasion and migration: implications for the pathogenesis of fetal growth restriction†.

Fetal growth restriction (FGR) is a condition in which a newborn fails to achieve his or her prospective hereditary growth potential. This condition is associated with high newborn mortality, second only to that associated with premature birth. FGR is associated with maternal, fetal, and placental abnormalities. Although the placenta is considered to be an important organ for supplying nutrition for fetal growth, research on FGR is limited, and treatment through the placenta remains challenging, as neither proper uterine intervention nor its pathogenesis have been fully elucidated. Yes-associated protein (YAP), as the effector of the Hippo pathway, is widely known to regulate organ growth and cancer development. Therefore, the correlation of the placenta and YAP was investigated to elucidate the pathogenic mechanism of FGR. Placental samples from humans and mice were collected for histological and biomechanical analysis. After investigating the location and role of YAP in the placenta by immunohistochemistry, we observed that YAP and cytokeratin 7 have corresponding locations in human and mouse placentas. Moreover, phosphorylated YAP (p-YAP) was upregulated in FGR and gradually increased as gestational age increased during pregnancy. Cell function experiments and mRNA-Seq demonstrated impaired YAP activity mediated by extracellular signal-regulated kinase inhibition. Established FGR-like mice also recapitulated a number of the features of human FGR. The results of this study may help to elucidate the association of FGR development with YAP and provide an intrauterine target that may be helpful in alleviating placental dysfunction.

Placental pathology in pregnancies complicated by fetal growth restriction: recurrence vs. new onset.

In an attempt to shed new light on the pathogenesis of fetal growth restriction (FGR), we aimed to study pregnancy characteristics, neonatal outcomes, and placental histopathological lesions of FGR pregnancies in two different subgroups: when developed after appropriate for gestational age (AGA) pregnancy and when developed after previous pregnancy with FGR. Pregnancy and placental reports of all singleton pregnancies complicated by FGR (defined as actual birthweight below the 10th percentile according to local birthweight nomograms) between 2008 and 2018 were reviewed. Included were only cases with previous delivery. Maternal background, neonatal outcomes, and placental histopathology were compared between FGR that occurred after FGR (recurrent FGR group) and FGR that occurred after an AGA pregnancy (FGR after AGA group). Placental lesions were classified according to the current "Amsterdam" criteria. Continuous variables were compared using the Student's t test or the Mann-Whitney test as appropriate. Categorical variables were compared using Chi-square or Fisher's exact test as appropriate. A total of 334 FGR cases with a previous delivery were included in the study. Of them, 111 cases constituted the recurrent FGR group and 223 constituted the FGR after AGA group. The recurrent FGR group was characterized by higher rates of maternal diabetes during pregnancy and hypertensive diseases (9% versus 2.7%, p = 0.01 and 19.8% versus 11.6%, p = 0.04). The FGR after AGA group was characterized by a higher rate of fetal vascular malperfusion (FVM) lesions (29.6% versus 18.0%, p = 0.02), and by lower mean birthweight (1842 ± 424.9 versus 1977.4 ± 412.2, p = 0.005), as compared to the recurrent FGR group. Recurrent FGR was associated with maternal background morbidities during pregnancy which represents a chronic repeated insult, while "new" FGR cases (those followed an AGA pregnancy) were characterized by a higher rate of FVM lesions and lower birthweight which probably represent an "accident" in placentation. These findings may suggest that different mechanisms of placental dysfunction exist in the two subgroups of FGR.

Cytokine profiles in maternal serum are candidates for predicting an optimal timing for the delivery in early-onset fetal growth restriction.

We examined whether maternal serum cytokine profiles of mothers with early-onset fetal growth restriction (FGR) were associated with delivery within 2 weeks after sampling during the third trimester. This exploratory prospective cross-sectional study included a total of 20 singleton fetuses with early-onset FGR and 31 healthy controls. Maternal serum samples during the early third trimester were analyzed for 23 cytokines. Of 20 fetuses with early-onset FGR, 14 had delivery within 2 weeks after sampling. Multivariate analysis revealed that maternal serum concentrations of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and soluble CD40 ligand (sCD40L) were independently associated with delivery within 2 weeks in early-onset FGR. Among cases of early-onset FGR, concentrations of almost all maternal serum cytokines were similar. Maternal serum sVEGFR-1 concentrations were high when delivery occurred within 2 weeks. Maternal serum sCD40L concentrations were elicited only in cases in which delivery within 2 weeks occurred due to fetal deterioration. We identified two biomarkers, one specific for FGR and the other dependent on severity, that were significant components of angiogenic activities and inflammation factors. Imbalances in serum protein expression may have a substantial effect on the pathogenesis of FGR.

Dysfunction of Tregs contributes to FGR pathogenesis via regulating Smads signalling pathway.

Fetal growth restriction (FGR) is ranked number two of most common complication of abnormal pregnancy worldwide. The pathogenesis of FGR is complicated due to multiple aetiologies and the exact mechanism for FGR development is currently unknown. T regulatory cells (Tregs) are proven to play central roles in the maintenance of normal pregnancy. Peripheral blood samples of 102 pregnant human were collected analysed using flow cytometry to identify Tregs. We found that reduced Tregs and down‐regulation of Foxp3 were observed in peripheral blood of FGR patients. In FGR mouse model, we have found that Tregs were not only reduced in spleen but also in placenta. In vitro, Foxp3 and its transcription regulatory signalling molecules, including P‐Smad2, P‐Smad3 and Smad4, were diminished as well. Inhibition on Foxp3 expression was partially reversed by overexpression of Smad2 and Smad4. In FGR patients, Western blot results revealed that Foxp3, P‐Smad2, P‐Smad3 and Smad4 expression was inhibited in placenta. Our preliminary result suggests that maternal‐foetal immune tolerance mediated by Tregs plays an essential role in the development of FGR. The inhibited expression of Foxp3 and down‐regulated Smad2/Smad3/Smad4 signalling pathway were involved in the FGR pathogenesis. Targeting maternal‐foetal immune tolerance through Tregs might represent a novel therapeutic option for FGR.

Potential role of microRNA-424 in regulating ERRγ to suppress trophoblast proliferation and invasion in fetal growth restriction

BackgroundAbnormal expression of estrogen-related receptor γ (ERRγ) protein is associated with fetal growth restriction (FGR). The upstream regulators of ERRγ are still unknown. ObjectiveTo evaluate the placental expression level of microRNA-424 (miR-424) and to demonstrate the relationship between miR-424 and FGR. MethodsThe expression levels of miR-424 were detected in FGR and control placentas. HTR-8/SVneo cells were transfected with mimics or inhibitors to increase or decrease the miR-424 expression level, respectively. The transwell and CCK-8 assays were used to determine trophoblast-derived cell line invasion and proliferation. The expression levels of miR-424, ERRγ, and 17 beta-hydroxysteroid dehydrogenase type 1 (HSD17B1) were detected by qRT-PCR and Western blotting. The relationship between miR-424, ERRγ, and HSD17B1 was determined by luciferase reporter assay. ResultsCompared to the normal pregnancy group, FGR placental tissues showed a significantly higher expression level of miR-424. The up-regulation of miR-424 decreased trophoblast-derived cell line invasion and proliferation. Down-regulation of miR-424 enhanced invasive and proliferative abilities of the cell lines. Over-expression of miR-424 reduced ERRγ protein levels and decreased both mRNA and protein levels of HSD17B1. Thus down-regulation of miR-424 induced protein expression of ERRγ and enhanced the mRNA and protein expressions of HSD17B1. MiR-424 probably mediated the expression of ERRγ via binding to sites other than mRNA 3′UTR. ConclusionMiR-424 may be associated with the pathogenesis of FGR by modulating trophoblast-derived cell line proliferation and invasion. MiR-424 may play a role in mediating the protein expressions of ERRγ and HSD17B1.

Disrupted placental serotonin synthetic pathway and increased placental serotonin: Potential implications in the pathogenesis of human fetal growth restriction

ObjectivesPlacental insufficiency contributes to altered maternal-fetal amino acid transfer, and thereby to poor fetal growth. An important placental function is the uptake of tryptophan and its metabolism to serotonin (5-HT) and kynurenine metabolites, which are essential for fetal development. We hypothesised that placental 5-HT content will be increased in pregnancies affected with fetal growth restriction (FGR). MethodsThe components of the 5-HT synthetic pathway were determined in chorionic villus samples (CVS) from small-for gestation (SGA) and matched control collected at 10–12 weeks of human pregnancy; and in placentae from third trimester FGR and gestation-matched control pregnancies using the Fluidigm Biomarker array for mRNA expression, the activity of the enzyme TPH and 5-HT concentrations using an ELISA. ResultsGene expression for the rate limiting enzymes, TPH1 and TPH2; 5-HT transporter, SLC6A4; and 5-HT receptors HTR5A, HTR5B, HTR1D and HTR1E were detected in all CVS and third trimester placentae. No significant difference in mRNA was observed in SGA compared with control. Although there was no significant change in TPH1 mRNA, the mRNA of TPH2 and SLC6A4 was significantly decreased in FGR placentae (p < 0.05), while 5-HT receptor mRNA was significantly increased in FGR compared with control (p < 0.01). Placental TPH enzyme activity was significantly increased with a concomitant increase in the total placental 5-HT concentrations in FGR compared with control. ConclusionThis study reports differential expression and activity of the key components of the 5-HT synthetic pathway associated with the pathogenesis of FGR. Further studies are required to elucidate the functional consequences of increased placental 5-HT in FGR pregnancies.

NLRP7 is increased in human idiopathic fetal growth restriction and plays a critical role in trophoblast differentiation.

Fetal growth restriction (FGR) the leading cause of perinatal mortality and morbidity is highly related to abnormal placental development, and placentas from FGR pregnancies are often characterized by increased inflammation. However, the mechanisms of FGR-associated inflammation are far from being understood. NLRP7, a member of a family of receptors involved in the innate immune responses, has been shown to be associated with gestational trophoblastic diseases. Here, we characterized the expression and the functional role of NLRP7 in the placenta and investigated its involvement in the pathogenesis of FGR. We used primary trophoblasts and placental explants that were collected during early pregnancy, and established trophoblast-derived cell lines, human placental villi, and serum samples from early pregnancy (n = 38) and from FGR (n = 40) and age-matched controls (n = 32). Our results show that NLRP7 (i) is predominantly expressed in the trophoblasts during the hypoxic period of placental development and its expression is upregulated by hypoxia and (ii) increases trophoblast proliferation ([3H]-thymidine) and controls the precocious differentiation of trophoblasts towards syncytium (syncytin 1 and 2 and β-hCG production and xCELLigence analysis) and towards invasive extravillous trophoblast (2D and 3D cultures). We have also demonstrated that NLRP7 inflammasome activation in trophoblast cells increases IL-1β, but not IL-18 secretion. In relation to the FGR, we demonstrated that major components of NLRP7 inflammasome machinery are increased and that IL-1β but not IL-18 circulating levels are increased in FGR. Altogether, our results identified NLRP7 as a critical placental factor and provided evidence for its deregulation in FGR. NLRP7 inflammasome is abundantly expressed by trophoblast cells. It is regulated by a key parameter of placental development, hypoxia. It controls trophoblast proliferation, migration, and invasion and exhibits anti-apoptotic role. NLRP7 machinery is deregulated in FGR pregnancies. KEY MESSAGES: NLRP7 inflammasome is abundantly expressed by trophoblast cells. It is regulated by a key parameter of placental development, hypoxia. It controls trophoblast proliferation, migration, and invasion and exhibits anti-apoptotic role. NLRP7 machinery is deregulated in FGR pregnancies.