TGFß signalling: a nexus between inflammation, placental health and preeclampsia throughout pregnancy.

BACKGROUND: The placenta is a unique and pivotal organ in reproduction, controlling crucial growth and cell differentiation processes that ensure a successful pregnancy. Placental development is a tightly regulated and dynamic process, in which the transforming growth factor beta (TGFß) superfamily plays a central role. This family of pleiotropic growth factors is heavily involved in regulating various aspects of reproductive biology, particularly in trophoblast differentiation during the first trimester of pregnancy. TGFß signalling precisely regulates trophoblast invasion and the cell transition from cytotrophoblasts to extravillous trophoblasts, which is an epithelial-to-mesenchymal transition-like process. Later in pregnancy, TGFß signalling ensures proper vascularization and angiogenesis in placental endothelial cells. Beyond its role in trophoblasts and endothelial cells, TGFß signalling contributes to the polarization and function of placental and decidual macrophages by promoting maternal tolerance of the semi-allogeneic foetus. Disturbances in early placental development have been associated with several pregnancy complications, including preeclampsia (PE) which is one of the severe complications. Emerging evidence suggests that TGFß is involved in the pathogenesis of PE, thereby offering a potential target for intervention in the human placenta. OBJECTIVE AND RATIONALE: This comprehensive review aims to explore and elucidate the roles of the major members of the TGFß superfamily, including TGFßs, bone morphogenetic proteins (BMPs), activins, inhibins, nodals, and growth differentiation factors (GDFs), in the context of placental development and function. The review focusses on their interactions within the major cell types of the placenta, namely trophoblasts, endothelial cells, and immune cells, in both normal pregnancies and pregnancies complicated by PE throughout pregnancy. SEARCH METHODS: A literature search was carried out using PubMed and Google Scholar, searching terms: 'TGF signalling preeclampsia', 'pregnancy TGF signalling', 'preeclampsia tgfß', 'preeclampsia bmp', 'preeclampsia gdf', 'preeclampsia activin', 'endoglin preeclampsia', 'endoglin pregnancy', 'tgfß signalling pregnancy', 'bmp signalling pregnancy', 'gdf signalling pregnancy', 'activin signalling pregnancy', 'Hofbauer cell tgfß signalling', 'placental macrophages tgfß', 'endothelial cells tgfß', 'endothelium tgfß signalling', 'trophoblast invasion tgfß signalling', 'trophoblast invasion Smad', 'trophoblast invasion bmp', 'trophoblast invasion tgfß', 'tgfß preeclampsia', 'tgfß placental development', 'TGFß placental function', 'endothelial dysfunction preeclampsia tgfß signalling', 'vascular remodelling placenta TGFß', 'inflammation pregnancy tgfß', 'immune response pregnancy tgfß', 'immune tolerance pregnancy tgfß', 'TGFß pregnancy NK cells', 'bmp pregnancy NK cells', 'bmp pregnancy tregs', 'tgfß pregnancy tregs', 'TGFß placenta NK cells', 'TGFß placenta tregs', 'NK cells preeclampsia', 'Tregs preeclampsia'. Only articles published in English until 2023 were used. OUTCOMES: A comprehensive understanding of TGFß signalling and its role in regulating interconnected cell functions of the main placental cell types provides valuable insights into the processes essential for successful placental development and growth of the foetus during pregnancy. By orchestrating trophoblast invasion, vascularization, immune tolerance, and tissue remodelling, TGFß ligands contribute to the proper functioning of a healthy maternal-foetal interface. However, dysregulation of TGFß signalling has been implicated in the pathogenesis of PE, where the shallow trophoblast invasion, defective vascular remodelling, decreased uteroplacental perfusion, and endothelial cell and immune dysfunction observed in PE, are all affected by an altered TGFß signalling. WIDER IMPLICATIONS: The dysregulation of TGFß signalling in PE has important implications for research and clinical practice. Further investigation is required to understand the underlying mechanisms, including the role of different ligands and their regulation under pathophysiological conditions, in order to discover new therapeutic targets. Distinguishing between clinically manifested subtypes of PE and studying TGFß signalling in different placental cell types holistically is an important first step. To put this knowledge into practice, pre-clinical animal models combined with new technologies are needed. This may also lead to improved human research models and identify potential therapeutic targets, ultimately improving outcomes for affected pregnancies and reducing the burden of PE.

Coumestrol induces oxidative stress and impairs migration and embryonic growth.

In brief: Healthy development of the placenta is dependent on trophoblast cell migration and reduced oxidative stress presence. This article describes how a phytoestrogen found in spinach and soy causes impaired placental development during pregnancy. Abstract: Although vegetarianism has grown in popularity, especially among pregnant women, the effects of phytoestrogens in placentation lack understanding. Factors such as cellular oxidative stress and hypoxia and external factors including cigarette smoke, phytoestrogens, and dietary supplements can regulate placental development. The isoflavone phytoestrogen coumestrol was identified in spinach and soy and was found to not cross the fetal-placental barrier. Since coumestrol could be a valuable supplement or potent toxin during pregnancy, we sought to examine its role in trophoblast cell function and placentation in murine pregnancy. After treating trophoblast cells (HTR8/SVneo) with coumestrol and performing an RNA microarray, we determined 3079 genes were significantly changed with the top differentially changed pathways related to the oxidative stress response, cell cycle regulation, cell migration, and angiogenesis. Upon treatment with coumestrol, trophoblast cells exhibited reduced migration and proliferation. Additionally, we observed increased reactive oxygen species accumulation with coumestrol administration. We then examined the role of coumestrol within an in vivo pregnancy by treating wildtype pregnant mice with coumestrol or vehicle from day 0 to 12.5 of gestation. Upon euthanasia, fetal and placental weights were significantly decreased in coumestrol-treated animals with the placenta exhibiting a proportional decrease with no obvious changes in morphology. Therefore, we conclude that coumestrol impairs trophoblast cell migration and proliferation, causes accumulation of reactive oxygen species, and reduces fetal and placental weights in murine pregnancy.

Maternal Iron Deficiency Alters Trophoblast Differentiation and Placental Development in Rat Pregnancy.

Iron deficiency, which occurs when iron demands chronically exceed intake, is prevalent in pregnant women. Iron deficiency during pregnancy poses major risks for the baby, including fetal growth restriction and long-term health complications. The placenta serves as the interface between a pregnant mother and her baby, and it ensures adequate nutrient provisions for the fetus. Thus, maternal iron deficiency may impact fetal growth and development by altering placental function. We used a rat model of diet-induced iron deficiency to investigate changes in placental growth and development. Pregnant Sprague-Dawley rats were fed either a low-iron or iron-replete diet starting 2 weeks before mating. Compared with controls, both maternal and fetal hemoglobin were reduced in dams fed low-iron diets. Iron deficiency decreased fetal liver and body weight, but not brain, heart, or kidney weight. Placental weight was increased in iron deficiency, due primarily to expansion of the placental junctional zone. The stimulatory effect of iron deficiency on junctional zone development was recapitulated in vitro, as exposure of rat trophoblast stem cells to the iron chelator deferoxamine increased differentiation toward junctional zone trophoblast subtypes. Gene expression analysis revealed 464 transcripts changed at least 1.5-fold (P < 0.05) in placentas from iron-deficient dams, including altered expression of genes associated with oxygen transport and lipoprotein metabolism. Expression of genes associated with iron homeostasis was unchanged despite differences in levels of their encoded proteins. Our findings reveal robust changes in placentation during maternal iron deficiency, which could contribute to the increased risk of fetal distress in these pregnancies.

The impact of periconceptional maternal lifestyle on clinical features and biomarkers of placental development and function: a systematic review.

BACKGROUND: Worldwide, placenta-related complications contribute to adverse pregnancy outcomes, such as pre-eclampsia, fetal growth restriction and preterm birth, with implications for the future health of mothers and offspring. The placenta develops in the periconception period and forms the interface between mother and embryo/fetus. An unhealthy periconceptional maternal lifestyle, such as smoking, alcohol and under- and over-nutrition, can detrimentally influence placental development and function. OBJECTIVE AND RATIONALE: The impact of maternal lifestyle on placental health is largely unknown. Therefore, we aim to summarize the evidence of the impact of periconceptional maternal lifestyle on clinical features and biomarkers of placental development and function throughout pregnancy. SEARCH METHODS: A comprehensive search in Medline, Embase, Pubmed, The Cochrane Library Web of Science and Google Scholar was conducted. The search strategy included keywords related to the maternal lifestyle, smoking, alcohol, caffeine, nutrition (including folic acid supplement intake) and body weight. For placental markers throughout pregnancy, keywords related to ultrasound imaging, serum biomarkers and histological characteristics were used. We included randomized controlled trials and observational studies published between January 2000 and March 2017 and restricted the analysis to singleton pregnancies and maternal periconceptional lifestyle. Methodological quality was scored using the ErasmusAGE tool. A protocol of this systematic review has been registered in PROSPERO International prospective register of systematic reviews (PROSPERO 2016:CRD42016045596). OUTCOMES: Of 2593 unique citations found, 82 studies were included. The median quality score was 5 (range: 0-10). The findings revealed that maternal smoking was associated with lower first-trimester placental vascularization flow indices, higher second- and third-trimester resistance of the uterine and umbilical arteries and lower resistance of the middle cerebral artery. Although a negative impact of smoking on placental weight was expected, this was less clear. Alcohol use was associated with a lower placental weight. One study described higher second- and third-trimester placental growth factor (PlGF) levels after periconceptional alcohol use. None of the studies looked at caffeine intake. Adequate nutrition in the first trimester, periconceptional folic acid supplement intake and strong adherence to a Mediterranean diet, were all associated with a lower resistance of the uterine and umbilical arteries in the second and third trimester. A low caloric intake resulted in a lower placental weight, length, breadth, thickness, area and volume. Higher maternal body weight was associated with a larger placenta measured by ultrasound in the second and third trimester of pregnancy or weighed at birth. In addition, higher maternal body weight was associated with decreased PlGF-levels. WIDER IMPLICATIONS: Evidence of the impact of periconceptional maternal lifestyle on placental health was demonstrated. However, due to poorly defined lifestyle exposures and time windows of investigation, unstandardized measurements of placenta-related outcomes and small sample sizes of the included studies, a cautious interpretation of the effect estimates is indicated. We suggest that future research should focus more on physiological consequences of unhealthy lifestyle during the critical periconception window. Moreover, we foresee that new evidence will support the development of lifestyle interventions to improve the health of mothers and their offspring from the earliest moment in life.

Angiopoietin 2 in placentation and tumor biology: The yin and yang of vascular biology.

There are several parallels between placental and tumor biology. Both require rapid acquisition of a blood supply to supply oxygen and nutrients, the placenta through neoangiogenesis and tumors by co-opting the existing vasculature. In addition, successful pregnancy also requires remodeling of the maternal uterine spiral arteries. Angiopoietins (Angs) are a family of angiogenic growth factors, the best studied being Ang-1 and Ang-2, which signal through the membrane tyrosine kinase receptor Tie2, and in simple terms have opposite effects with Ang-1 acting to stabilize newly formed blood vessels and Ang-2 having a destabilizing effect. The roles of Ang-1, and in particular Ang-2 in placental and tumor biology are discussed in this review.

The YY1/MMP2 axis promotes trophoblast invasion at the maternal-fetal interface.

YY1 is a sequence-specific DNA-binding transcription factor that has many important biological roles. However, its function in trophoblasts at the maternal-fetal interface remains to be elucidated. In this study, we used an mRNA microarray and reverse transcription qPCR and compared the YY1 mRNA expression level in trophoblasts between patients with recurrent miscarriage (RM) and healthy control subjects. Our results revealed that YY1 mRNA expression was significantly lower in the trophoblasts of the RM group compared with the healthy control group. Furthermore, immunofluorescence and immunohistochemical data showed that YY1 was highly expressed in human placental villi during early pregnancy, especially in cytotrophoblast cells and invasive extravillous trophoblasts, and it was expressed at a much lower level in the placental villi of term pregnancy. YY1 overexpression enhanced, and knockdown repressed, the invasion and proliferation of trophoblasts. Antibody array screening revealed that YY1 significantly promoted MMP2 expression in trophoblasts. Bioinformatics analysis identified three YY1-binding sites in the MMP2 promoter region, and chromatin immunoprecipitation analysis verified that YY1 binds directly to its promoter region. Importantly, inhibition of YY1 by siRNA clearly decreased trophoblast invasion in an ex vivo explant culture model. Overall, our findings revealed a new regulatory pathway of YY1/MMP2 in trophoblast cell invasion during early pregnancy and indicated that YY1 may be involved in the pathogenesis of RM.

Biochemical parameters in the blood of Holstein calves given immunoglobulin Y-supplemented colostrums.

BACKGROUND: In any calf rearing system it is desirable to obtain healthy animals, and reduce morbidity, mortality, and economic losses. Bovine syndesmochorial placentation prevents the direct transfer of bovine immunoglobulins to the fetus, and calves are born hypogammaglobulinemic. These calves therefore require colostrum immediately after birth. Colostrum is rich in immunoglobulins (Ig) and its consumption results in the transfer of passive immunity to calves. The Ig absorption occurs within the first 12 h after birth. Immunoglobulin Y (IgY), derived from chicken egg yolk, has been used in the prevention and control of diseases affecting calves because it is very similar in structure and function to immunoglobulin G (IgG). In the current study, we sought to establish whether administration routes of colostrum supplemented with avian IgY affected passive immunity in calves. RESULTS: No significant differences were observed with respect to route of administration for colostrum. However, we did observe some differences in certain interactions between the various treatments. Calves fed colostrum containing egg yolk had higher levels of TP, ALB, and IgG, along with increased GGT activity. CONCLUSIONS: Our results suggest that supplementing colostrum with egg yolk has a beneficial effect when given to calves, regardless of administration route.