scholarly journals Inflammation in rat pregnancy inhibits spiral artery remodeling leading to fetal growth restriction and features of preeclampsia

2014 ◽  
Vol 211 (1) ◽  
pp. 165-179 ◽  
Author(s):  
Tiziana Cotechini ◽  
Maria Komisarenko ◽  
Arissa Sperou ◽  
Shannyn Macdonald-Goodfellow ◽  
Michael A. Adams ◽  
...  
Keyword(s):  
Fetal Growth ◽  
Pregnancy Complications ◽  
Fetal Growth Restriction ◽  
Nitrosative Stress ◽  
Growth Restriction ◽  
Trophoblast Invasion ◽  
Spiral Artery ◽  
Transdermal Administration ◽  
Pregnant Rats ◽  
Maternal Inflammation

Fetal growth restriction (FGR) and preeclampsia (PE) are often associated with abnormal maternal inflammation, deficient spiral artery (SA) remodeling, and altered uteroplacental perfusion. Here, we provide evidence of a novel mechanistic link between abnormal maternal inflammation and the development of FGR with features of PE. Using a model in which pregnant rats are administered low-dose lipopolysaccharide (LPS) on gestational days 13.5–16.5, we show that abnormal inflammation resulted in FGR mediated by tumor necrosis factor-α (TNF). Inflammation was also associated with deficient trophoblast invasion and SA remodeling, as well as with altered uteroplacental hemodynamics and placental nitrosative stress. Moreover, inflammation increased maternal mean arterial pressure (MAP) and was associated with renal structural alterations and proteinuria characteristic of PE. Finally, transdermal administration of the nitric oxide (NO) mimetic glyceryl trinitrate prevented altered uteroplacental perfusion, LPS-induced inflammation, placental nitrosative stress, renal structural and functional alterations, increase in MAP, and FGR. These findings demonstrate that maternal inflammation can lead to severe pregnancy complications via a mechanism that involves increased maternal levels of TNF. Our study provides a rationale for the use of antiinflammatory agents or NO-mimetics in the treatment and/or prevention of inflammation-associated pregnancy complications.

L3. Trophoblast invasion and spiral artery transformation in pre-eclampsia and fetal growth restriction

2011 ◽  
Vol 1 (3-4) ◽  
pp. 239-240
Author(s):  
Fiona Lyall ◽  
Judith Bulmer ◽  
Robert Pijnenborg ◽  
Helen Simpson ◽  
Stephen Robson
Keyword(s):  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Growth Restriction ◽  
Trophoblast Invasion ◽  
Spiral Artery

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

2020 ◽  
Vol 103 (4) ◽  
pp. 866-879
Author(s):  
Hao Wang ◽  
Ping Xu ◽  
Xiaofang Luo ◽  
Mingyu Hu ◽  
Yamin Liu ◽  
...  
Keyword(s):  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Cell Function ◽  
Hippo Pathway ◽  
Growth Restriction ◽  
Growth Potential ◽  
Biomechanical Analysis ◽  
Trophoblast Invasion ◽  
Invasion And Migration ◽  
And Migration

Abstract 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.

scholarly journals Levels of miR-374 increase in BeWo b30 cells exposed to hypoxia

2021 ◽  
Author(s):  
EN Knyazev ◽  
SYu Paul
Keyword(s):  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Target Genes ◽  
Expression Profiles ◽  
Growth Restriction ◽  
Trophoblast Invasion ◽  
Placental Development ◽  
Cell Potential ◽  
Bewo B30 ◽  
Next Generation Sequencing Ngs

In humans, trophoblast hypoxia during placental development can be a cause of serious pregnancy complications, such as preeclampsia and fetal growth restriction. The pathogenesis of these conditions is not fully clear and may be associated with changed expression of some genes and regulatory molecules, including miRNA, in trophoblast cells. The aim of this study was to analyze miRNA profiles and measure the expression of their target genes in a model of trophoblast hypoxia. Human choriocarcinoma BeWo b30 cells were used as a trophoblast model. Hypoxia was induced by cobalt chloride (CoCl2) and an oxyquinoline derivative. MRNA and miRNA expression profiles were evaluated by means of next generation sequencing (NGS); the expression of individual genes was analyzed by PCR. We studied the secondary structure of mRNAs of target genes for those miRNAs whose expression had changed significantly and analyzed potential competition between these miRNAs for the binding site. The observed changes in the expression of the key genes involved in the response to hypoxia confirmed the feasibility of using CoCl2 and the oxyquinoline derivative as hypoxia inducers. The analysis revealed an increase in miR-374 levels following the activation of the hypoxia pathway in our trophoblast model. The changes were accompanied by a reduction in FOXM1 mRNA expression; this mRNA is a target for hsa-miR-374a-5p and hsa-miR374b-5p, which can compete with hsa-miR-21-5p for the binding sites on FOXM1 mRNA. The involvement of FOXM1 in the regulation of the invasive cell potential suggests the role of miR-374 and FOXM1 in the pathogenesis of disrupted trophoblast invasion during placental development as predisposing for fetal growth restriction and preeclampsia.

scholarly journals Differences in Placental Imprinted Gene Expression across Preeclamptic and Non-Preeclamptic Pregnancies

Genes ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 1146
Author(s):  
Maya A. Deyssenroth ◽  
Qian Li ◽  
Carlos Escudero ◽  
Leslie Myatt ◽  
Jia Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fetal Growth ◽  
Pregnancy Complications ◽  
Fetal Growth Restriction ◽  
Late Onset ◽  
Critical Role ◽  
Growth Restriction ◽  
Imprinted Genes ◽  
Imprinted Gene ◽  
Expression Levels

Preeclampsia is a multi-systemic syndrome that presents in approximately 5% of pregnancies worldwide and is associated with a range of subsequent postpartum and postnatal outcomes, including fetal growth restriction. As the placenta plays a critical role in the development of preeclampsia, surveying genomic features of the placenta, including expression of imprinted genes, may reveal molecular markers that can further refine subtypes to aid targeted disease management. In this study, we conducted a comprehensive survey of placental imprinted gene expression across early and late onset preeclampsia cases and preterm and term normotensive controls. Placentas were collected at delivery from women recruited at the Magee-Womens Hospital prenatal clinics, and expression levels were profiled across 109 imprinted genes. We observed downregulation of placental Mesoderm-specific transcript (MEST) and Necdin (NDN) gene expression levels (false discovery rate (FDR) < 0.05) among early onset preeclampsia cases compared to preterm controls. No differences in placental imprinted gene expression were observed between late onset preeclampsia cases and term controls. While few studies have linked NDN to pregnancy complications, reductions in MEST expression levels, as observed in our study, are consistently reported in the literature in relation to various pregnancy complications, including fetal growth restriction, suggesting a potential role for placental MEST expression as a biosensor of an adverse in utero environment.

scholarly journals Circulating Maternal sFLT1 (Soluble fms-Like Tyrosine Kinase-1) Is Sufficient to Impair Spiral Arterial Remodeling in a Preeclampsia Mouse Model

Hypertension ◽  
2021 ◽  
Author(s):  
Rebekka Vogtmann ◽  
Jacqueline Heupel ◽  
Florian Herse ◽  
Mahsa Matin ◽  
Henning Hagmann ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Aortic Wall ◽  
Growth Restriction ◽  
Trophoblast Invasion ◽  
Wall Thickening ◽  
Uterine Natural Killer Cells ◽  
Maternal Contribution ◽  
Maternal Hypertension

One driving factor for developing preeclampsia—a pregnancy disorder, often associated with poor spiral artery (SpA)-remodeling and fetal growth restriction—is the anti-angiogenic sFLT1 (soluble fms-like tyrosine kinase-1), which is found to be highly upregulated in preeclampsia patients. The sFLT1-mediated endothelial dysfunction is a common theory for the manifestation of maternal preeclampsia symptoms. However, the influence of sFLT1 on SpA-remodeling and the link between placental and maternal preeclampsia symptoms is less understood. To dissect the hsFLT1 (human sFLT1) effects on maternal and/or fetoplacental physiology in preeclampsia, sFLT1-transgenic mice with systemic hsFLT1 overexpression from midgestation onwards were used. SpA-remodeling was analyzed on histological and molecular level in placental/mesometrial triangle tissues. Maternal kidney and aorta morphology was investigated, combined with blood pressure measurements via telemetry. hsFLT1 overexpression resulted in maternal hypertension, aortic wall thickening, and elastin breakdown. Furthermore, maternal kidneys showed glomerular endotheliosis, podocyte damage, and proteinuria. preeclampsia symptoms were combined with fetal growth restriction already at the end of the second trimester and SpA-remodeling was strongly impaired as shown by persisted vascular smooth muscle cells. This phenotype was associated with shallow trophoblast invasion, delayed presence of uterine natural killer cells, and altered lymphatic angiogenesis. Overall, this study showed that circulating maternal hsFLT1 is sufficient to induce typical maternal preeclampsia-like symptoms in mice and impair the SpA-remodeling independent from the fetoplacental compartment, revealing new insights into the interaction between the placental and maternal contribution of preeclampsia.

scholarly journals Nutrient sensor signaling pathways and cellular stress in fetal growth restriction

2019 ◽  
Vol 62 (2) ◽  
pp. R155-R165 ◽  
Author(s):  
Bethany Hart ◽  
Elizabeth Morgan ◽  
Emilyn U Alejandro
Keyword(s):  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Cellular Stress ◽  
Nutrient Sensing ◽  
Growth Restriction ◽  
Trophoblast Invasion ◽  
Supporting Evidence ◽  
Placental Development ◽  
Nutrient Regulation ◽  
Placental Perfusion

Fetal growth restriction is one of the most common obstetrical complications resulting in significant perinatal morbidity and mortality. The most frequent etiology of human singleton fetal growth restriction is placental insufficiency, which occurs secondary to reduced utero-placental perfusion, abnormal placentation, impaired trophoblast invasion and spiral artery remodeling, resulting in altered nutrient and oxygen transport. Two nutrient-sensing proteins involved in placental development and glucose and amino acid transport are mechanistic target of rapamycin (mTOR) and O-linked N-acetylglucosamine transferase (OGT), which are both regulated by availability of oxygen. Impairment in either of these pathways is associated with fetal growth restriction and accompanied by cellular stress in the forms of hypoxia, oxidative and endoplasmic reticulum (ER) stress, metabolic dysfunction and nutrient starvation in the placenta. Recent evidence has emerged regarding the potential impact of nutrient sensors on fetal stress response, which occurs in a sexual dysmorphic manner, indicating a potential element of genetic gender susceptibility to fetal growth restriction. In this mini review, we focus on the known role of mTOR and OGT in placental development, nutrient regulation and response to cellular stress in human fetal growth restriction with supporting evidence from rodent models.

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