Placenta最新文献

{"title":"Feto-placental vascular structure and in silico haemodynamics: Of mice, rats, and human","authors":"Nikhilesh Bappoo ,&nbsp;Yutthapong Tongpob ,&nbsp;Matina Hakim ,&nbsp;Jenny Myers ,&nbsp;Emma Panting ,&nbsp;Karen E. Chapman ,&nbsp;Adrian J.W. Thomson ,&nbsp;Carmel M. Moran ,&nbsp;Lachlan J. Kelsey ,&nbsp;Vijayalakshmi Srinivasan ,&nbsp;Joanna L. James ,&nbsp;Alys R. Clark ,&nbsp;Barry J. Doyle ,&nbsp;Caitlin S. Wyrwoll","doi":"10.1016/j.placenta.2024.10.020","DOIUrl":"10.1016/j.placenta.2024.10.020","url":null,"abstract":"<div><h3>Introduction</h3><div>The complex arborization of the feto-placental vasculature is crucial for optimal fetal nutrition, waste exchange and ultimately, development. Ethical and experimental limitations constrain research into the human placenta, hence experimental animal models such as mice and rats, are crucial to understand placental function. It is unclear how well the mouse and rat feto-placental vascular structure emulates human. Moreover, the implications of differences in vascular structure, especially in arborization, for placental function remain unclear.</div></div><div><h3>Methods</h3><div>We use micro-computed tomography imaging, high frequency Doppler ultrasound and computational fluid dynamics to characterize feto-placental vasculature structure and haemodynamics in mice, rats, and human.</div></div><div><h3>Results</h3><div>Our data suggest that despite structural differences between rat and mouse placenta, haemodynamics are similar and that both hold applicability to investigating feto-placental structure and function. We show that human cotyledons demonstrate vascularity-dependent haemodynamic behaviour (including flow deceleration and oxygen exchange) similar to rodents and can be analysed in the same spectrum as rodents. Finally, we show strong structure-function relationships when interspecies datasets are combined; notably, we demonstrate that surrogate measures such as vascularity, can be used to estimate placental oxygen exchange function.</div></div><div><h3>Discussion</h3><div>Pre-clinical placental research utilising rat and mouse placentae to understand the impact of feto-placental arborization on placental function and fetal development can inform the human context.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"158 ","pages":"Pages 175-184"},"PeriodicalIF":3.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methylation and expression of imprinted genes in circulating extracellular vesicles from women experiencing early onset preeclampsia","authors":"Uma Shinde ,&nbsp;Kushaan Khambata ,&nbsp;Sanketa Raut ,&nbsp;Aishwarya Rao ,&nbsp;Vandana Bansal ,&nbsp;Niranjan Mayadeo ,&nbsp;Dhanjit kumar Das ,&nbsp;Taruna Madan ,&nbsp;Vinoth Prasanna Gunasekaran ,&nbsp;Nafisa Huseni Balasinor","doi":"10.1016/j.placenta.2024.10.019","DOIUrl":"10.1016/j.placenta.2024.10.019","url":null,"abstract":"<div><h3>Introduction</h3><div>Preeclampsia (PE) is a pregnancy complication marked by high blood pressure, posing risk to maternal and fetal health. \"Genomic imprinting\", an epigenetic phenomenon regulated by DNA methylation at Differently Methylated Regions (DMR's), influences placental development. Research on circulating extracellular vesicles (EVs) in PE suggests them as potential source for early biomarkers, but methylation status of EV-DNA in Preeclampsia is not reported yet.</div></div><div><h3>Methods</h3><div>This study examines the methylation and expression profile of imprinted genes - <em>PEG10</em>, <em>PEG3</em>, <em>MEST</em>, and <em>DLK1</em> in circulating EVs of 1^st and 3^rd trimester control and early onset preeclampsia (EOPE) pregnant women (n = 15) using pyrosequencing and qRT-PCR respectively.</div></div><div><h3>Results</h3><div>In 1^st trimester, <em>PEG3</em> was significantly hypermethylated, whereas no significant methylation changes were noted in <em>PEG10</em> and <em>MEST</em> in EOPE. In 3^rd trimester, significant hypomethylation in <em>PEG10</em>, <em>PEG3</em> and IGDMR was observed whereas significant hypermethyaltion noted in <em>MEST</em>. mRNA expression of <em>PEG10</em>, <em>PEG3</em> and <em>DLK1</em> was not affected in circulating EVs of 1^st trimester EOPE. However, in 3^rd trimester significant increased expression in <em>PEG10</em>, <em>PEG3</em> and <em>DLK1</em> noted. <em>MEST</em> expression was reduced in 3^rd trimester EOPE. No correlation was observed between average DNA methylation and gene expression in <em>PEG10</em> and <em>PEG3</em> in 1^st trimester. However, in 3^rd trimester, significant negative correlation was noted in <em>PEG10</em> (r = −0.426, p = 0.04), <em>PEG3</em> (r = −0.496, p = 0.01), <em>MEST</em> (r = −0.398, p = 0.03) and <em>DLK1</em> (r = −0.403, p = 0.03).</div></div><div><h3>Discussion</h3><div>The results of our study strengthen the potential of circulating EVs from maternal serum as non-invasive indicators of placental pathophysiology, including preeclampsia.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"158 ","pages":"Pages 206-215"},"PeriodicalIF":3.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MiR-142-5p mediated Nrf2 dysregulation in gestational diabetes mellitus and its impact on placental angiogenesis","authors":"K.L. Milan ,&nbsp;V. Gayatri ,&nbsp;Kumaran Kriya ,&nbsp;N. Sanjushree ,&nbsp;Sri Vishwanathan Palanivel ,&nbsp;M. Anuradha ,&nbsp;Kunka Mohanram Ramkumar","doi":"10.1016/j.placenta.2024.10.021","DOIUrl":"10.1016/j.placenta.2024.10.021","url":null,"abstract":"<div><h3>Introduction</h3><div>Gestational diabetes mellitus (GDM) presents significant risks during pregnancy, including adverse perinatal outcomes and placental dysfunction. Impaired angiogenesis, involving crucial factors like Vascular Endothelial Growth Factor (VEGF), contributes to these complications. The Nrf2/Keap1 pathway, crucial for vascular redox homeostasis, has been linked to GDM-associated angiogenesis dysregulation.</div></div><div><h3>Methods</h3><div>This study aimed to investigate the molecular mechanisms underlying placental Nrf2 regulation, focusing on angiomiRs, key regulators of angiogenesis in GDM. Computational analysis identified miR-142-5p targeting Nrf2 mRNA. Expression levels of miR-142-5p were assessed in GDM placenta and correlated with Nrf2 expression. Experimental validation utilized human trophoblastic cell lines (BeWo) exposed to hyperglycemic conditions, assessing the effects of anti-miR-142 transfection on Nrf2 expression and angiogenic marker levels.</div></div><div><h3>Results</h3><div>miR-142-5p expression was significantly downregulated in GDM placenta, correlating positively with Nrf2 expression. In BeWo cells exposed to hyperglycemia, anti-miR-142 transfection notably increased Nrf2 expression alongside angiogenic marker levels, confirming the computational predictions.</div></div><div><h3>Discussion</h3><div>Our findings highlight the pivotal role of miRNAs in GDM-associated impaired angiogenesis by modulating Nrf2 expression. Understanding these molecular mechanisms provides insights into potential therapeutic targets for improving pregnancy outcomes in GDM cases.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"158 ","pages":"Pages 192-199"},"PeriodicalIF":3.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Placental volume at gestational week 27 and subsequent fetal growth: An observational study","authors":"Helene Fjeldvik Peterson ,&nbsp;Kari Flo ,&nbsp;Silje Sommerfelt ,&nbsp;Vigdis Hillestad","doi":"10.1016/j.placenta.2024.10.022","DOIUrl":"10.1016/j.placenta.2024.10.022","url":null,"abstract":"<div><h3>Objectives</h3><div>To study if placental volume and placental to fetal ratio at gestational week (GW) 27 correlate with subsequent fetal growth. We also investigated whether the 1/3 smallest and 1/3 largest fetuses have different growth potential depending on placental volume.</div></div><div><h3>Methods</h3><div>Placental and fetal volume was measured by magnetic resonance imaging (MRI) at GW 27 and 37 in 86 singleton pregnancies. Placental to fetal ratio was calculated as placental volume/fetal volume. Growth was calculated as [(fetal volume at GW 37 – fetal volume at GW 27)/number of days between the MRI examinations]. To explore whether a higher placental volume affected growth of small and large fetuses differently, we performed separate analyses of the 1/3 smallest and 1/3 largest fetuses with placental volume under and above the median at GW 27.</div></div><div><h3>Results</h3><div>We found a positive correlation of both placental volume and placental to fetal ratio at GW 27 with average growth velocity, r = 0.51 (p &lt; 0.001) and r = 0.33 (p = 0.002) respectively. The correlation between fetal volume at GW 27 and average growth velocity was r = 0.48 (p &lt; 0.001). The small fetuses had significantly lower average growth velocity if the placental volume was low compared to if the placental volume was high, 22 (SD 3) cm³/day versus 25 (SD 3) cm³/day, p = 0.02. Among the large fetuses, placental volume did not significantly affect growth.</div></div><div><h3>Conclusions</h3><div>Placental volume and placental to fetal ratio at GW 27 were positively correlated with subsequent fetal growth. Possibly, placental size is an indicator of fetal growth potential, especially among small fetuses.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"158 ","pages":"Pages 200-205"},"PeriodicalIF":3.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Placenta-associated biomarkers and pregnancy outcome in HPA-1a alloimmunization: A prospective cohort study","authors":"Nora Hersoug Nedberg ,&nbsp;Mona Nystad ,&nbsp;Maria Therese Ahlen ,&nbsp;Eirin Listau Bertelsen ,&nbsp;Katarzyna Guz ,&nbsp;Małgorzata Uhrynowska ,&nbsp;Marzena Dębska ,&nbsp;Agnieszka Gierszon ,&nbsp;Agnieszka Orzińska ,&nbsp;Anne Husebekk ,&nbsp;Ewa Brojer ,&nbsp;Anne Cathrine Staff ,&nbsp;Heidi Tiller","doi":"10.1016/j.placenta.2024.10.014","DOIUrl":"10.1016/j.placenta.2024.10.014","url":null,"abstract":"<div><h3>Introduction</h3><div>Fetal and neonatal alloimmune thrombocytopenia (FNAIT) results from parental incompatibility in human platelet antigens (HPA) and subsequent maternal sensitization. The HPA-1a epitope is also expressed on placental tissue. Chronic placental inflammation and lower birth weight is observed more often in HPA-1a alloimmunized pregnancies, suggesting a placental component in the pathophysiology of FNAIT. Today, prediction of FNAIT severity is limited. The aim of the study was to investigate whether dysregulated maternal angiogenic proteins are associated with neonatal outcome in HPA-1a alloimmunized pregnancies.</div></div><div><h3>Material and methods</h3><div>Eighty-seven HPA-1a negative pregnant women were identified from a large prospective screening study in Poland (PREVFNAIT) including 43 HPA-1a immunized and 44 non-immunized controls. Placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) were measured in maternal plasma from 2nd and 3rd trimester by enzyme-linked immunosorbent assay and levels/ratios were compared between study groups, using uni- and multivariable analyses. Main outcome measures were either classic FNAIT-related (severe thrombocytopenia, petechia, intracranial hemorrhage), placenta-related (small for gestational age) or a composite variable combining them all.</div></div><div><h3>Results</h3><div>There were no significant differences in plasma concentrations of sFlt-1, PlGF, sEng nor sFlt-1/PlGF ratio when comparing immunized and non-immunized pregnancies. Among HPA-1a alloimmunized pregnancies, increasing levels of the sFlt-1 protein in 3rd trimester were significantly associated with lower neonatal platelet count (multivariable linear regression, p = 0.024). Increased sFlt-1 and sFlt-1/PlGF ratio in 3rd trimester were significantly associated with higher odds of a composite adverse neonatal outcome in alloimmunized pregnancies (multivariable logistic regression, p = 0.029 and p = 0.019, respectively).</div></div><div><h3>Conclusion</h3><div>An anti-angiogenic profile in HPA-1a alloimmunized mothers is associated with a composite adverse neonatal outcome. This suggests that sFlt-1 and the sFlt-1/PlGF ratio may assist in predelivery risk stratification and clinical management decisions for FNAIT.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"158 ","pages":"Pages 185-191"},"PeriodicalIF":3.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142561303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelin-1 potentiated constriction in preeclampsia placental veins: Role of ETAR/ETBR/CaV1.2/CALD1","authors":"Hongyu Su ,&nbsp;Min Li ,&nbsp;Na Li ,&nbsp;Yingying Zhang ,&nbsp;Yun He ,&nbsp;Ze Zhang ,&nbsp;Yumeng Zhang ,&nbsp;Qinqin Gao ,&nbsp;Zhice Xu ,&nbsp;Jiaqi Tang","doi":"10.1016/j.placenta.2024.10.011","DOIUrl":"10.1016/j.placenta.2024.10.011","url":null,"abstract":"<div><h3>Background</h3><div>Placenta plays a vital role in preeclampsia. The present study investigated the role of endothelin-1 (ET-1) and its receptors in preeclampsia placenta.</div></div><div><h3>Method</h3><div>Placenta samples were collected from normal and preeclampsia pregnancies, with one single fetus. Placental chorionic plate vessel tone was measured with DMT using vasoactive agents with or without antagonists. Role of L-type voltage-dependent calcium channels (CaV1.2) in single smooth muscle cell was detected using whole-cell patch clamp. PCR, Western blot, and ELISA was used to detect molecule expressions. Placental vessel explants and human umbilical vein smooth muscle cell (HUVSMC) were exposed to ET-1 treatment with or without antagonists. Human umbilical vein endothelial cell (HUVEC) and pregnant sheep was exposed to hypoxic condition, simulating preeclampsia.</div></div><div><h3>Results</h3><div>ET-1 and IRL1620 mediated stronger contractions in preeclampsia placental veins, despite unchanged ETAR and decreased ETBR expression. Comparing with control, there was higher ET-1 in umbilical plasma, maternal plasma, and placental vessels from preeclampsia. <em>In utero</em> hypoxia increased plasma ET-1 in fetal lambs and ewes. Hypoxia promoted ET-1 production in HUVEC. Role and expression of CaV1.2 was decreased in preeclampsia placental vessels, while high-molecular-weight caldesmon (CALD1), the marker of contractile phenotype of smooth muscle cells, was significantly increased. ET-1 treatment increased CALD1 in placental explants and in HUVSMC via ETAR/ETBR.</div></div><div><h3>Conclusion</h3><div>The present study firstly demonstrated ET-1 induced greater contraction in preeclampsia placental chorionic plate veins via ETAR/ETBR, instead of via weaker CaV1.2. <em>In utero</em> hypoxia promoted plasma ET-1 in fetal lambs and ewe, similar to that in preeclampsia. ET-1, binding with ETAR/ETBR increased CALD1, which was associated with stronger contraction in preeclampsia. The data provided important information in preeclampsia onset.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"158 ","pages":"Pages 165-174"},"PeriodicalIF":3.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A systematic review and risk of bias analysis of in vitro studies on trophoblast response to immunological triggers.","authors":"Bart Christiaan Hameete, Torsten Plösch, Astrid Hogenkamp, Lucianne Groenink","doi":"10.1016/j.placenta.2024.10.010","DOIUrl":"https://doi.org/10.1016/j.placenta.2024.10.010","url":null,"abstract":"<p><p>An increasing amount of evidence suggests that immune responses may affect trophoblast functioning, which in turn may play a role in gestational disorders and fetal development. This systematic review offers the first summary of in vitro studies on the trophoblast response to immunological triggers, in conjunction with a risk of bias analysis. A search in Pubmed and Embase yielded 110 relevant studies. Primary trophoblasts were the most commonly used cell type, but trophoblast subtypes were not always defined. Similarly, the exact natures of trophoblast cell lines were sometimes unclear. Cytokines and Toll-like receptor agonists were often used as interventions, but most studies focused on a select few substances such as tumor necrosis factor-α and lipopolysaccharide. In regard to the outcome parameters, some important trophoblast functions, such as hormone production and barrier formation were underrepresented. Whether or not risk of bias was high varied strongly between types of bias. Risk of selection bias, for example, was usually low. However, none of the included studies mentioned blinding or plate randomization. Only a select few studies mentioned passage numbers, use of vehicle control or conflict of interest. In conclusion, better characterization of trophoblast subtypes and a broader range of studied interventions and outcome parameters would contribute to a more complete understanding of trophoblast responses to immune stimuli. Additionally, researchers are encouraged to replicate experiments and pay close attention when setting up and writing down methodologies, in order to improve the reproducibility and translatability of their work.</p>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vivo placental gene modulation via sonoporation.","authors":"Lance G A Nunes, Fredrick J Rosario, Johann Urschitz","doi":"10.1016/j.placenta.2024.10.015","DOIUrl":"https://doi.org/10.1016/j.placenta.2024.10.015","url":null,"abstract":"<p><p>Placental dysregulation frequently results in pregnancy complications that impact fetal well-being and potentially predispose the infant to diseases later in life. Thus, efforts to understand the molecular mechanisms underlying placental disorders are crucial to aid the development of effective treatments to restore placental function. Currently, the most common methods used for trophoblast-specific gene modulation in the laboratory are transgenic animals and lentiviral trophectoderm transduction. The generation of transgenic animal lines is costly and requires a considerable amount of time to generate and maintain, while the integration preference of lentiviruses, actively transcribed genes, may result in genotoxicity. Therefore, there is much interest in the development of non-viral in vivo transfection techniques for use in both research and clinical settings. Herein, we describe a non-viral, minimally invasive method for in vivo placental gene modulation through sonoporation, an ultrasound-mediated transfection technique wherein the application of ultrasound on target tissues is used to direct the uptake of DNA vectors. In this method, plasmids are bound to lipid microbubbles, which are then injected into the maternal bloodstream and ultimately delivered to the placenta when subjected to low-frequency ultrasound. Syncytiotrophoblasts are directly exposed to maternal blood and, therefore highly accessible to therapeutic agents in the maternal circulation. This technique can be used to modulate gene expression and, subsequently, the function of the placenta, circumventing the requirement to generate transgenic animals. Sonoporation also offers a safer alternative to existing viral techniques, making it not only an advantageous research tool but also a potentially adaptable technique in clinical settings.</p>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The autophagy process and oxidized LDL independently modulate the invasion and differentiation of extravillous trophoblastic cells to an endothelial-like phenotype in normoxia","authors":"Lorena Carvajal ,&nbsp;Rodrigo Escalona ,&nbsp;Patricia Rivera ,&nbsp;Macarena Aguilera-Olguin ,&nbsp;María Paz Hernández-Cáceres ,&nbsp;Jaime Gutiérrez ,&nbsp;Eugenia Morselli ,&nbsp;Andrea Leiva","doi":"10.1016/j.placenta.2024.10.017","DOIUrl":"10.1016/j.placenta.2024.10.017","url":null,"abstract":"<div><h3>Introduction</h3><div>The mechanisms leading to proper placentation are not fully understood. Extravillous trophoblasts (EVTs) are crucial for placentation through invasion and vascular remodeling, which, when impaired, promote a poor placentation. How autophagy could regulate EVTs function and the study of regulators of these processes, such as oxidized low-density lipoproteins (ox-LDL), could contribute to better understand events associated with pregnancy complications related to abnormal placental development, such as preeclampsia (PE).</div></div><div><h3>Aim</h3><div>To investigate the role of autophagy and oxidized LDL (ox-LDL) in invasion and endothelial-like phenotype acquisition of a model of EVTs, as well as to determine the levels of autophagy flux markers in control and PE placentas.</div></div><div><h3>Methods</h3><div>Invasion and endothelial-like phenotype acquisition assays were performed in a cell line model of first trimester EVTs: HTR-8/SVneo cultured in normoxia (oxygen concentration of 20 %), in the absence or the presence of the autophagy inhibitor bafilomycin or/and ox-LDL. Markers of autophagic flux were evaluated in human term placentas.</div></div><div><h3>Results</h3><div>Autophagy is essential for EVTs to acquire an endothelial-like phenotype but does not affect invasion. Conversely, ox-LDL decreases invasion and reticular structures formation, independent of autophagy. At pregnancy term, the levels of the autophagy markers LC3 and p62 are deregulated in the trophoblast cells of PE placentas.</div></div><div><h3>Conclusion</h3><div>Autophagy is necessary for proper endothelial-like phenotype acquisition in HTR-8/SVneo cultured in normoxia, and ox-LDL impairs this process as well as the invasion of EVTs by a mechanism independent of autophagy. Changes in autophagy and/or in the concentration of ox-LDL could affect placental vascular remodeling.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"158 ","pages":"Pages 263-274"},"PeriodicalIF":3.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142625039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Puerarin alleviates symptoms of preeclampsia through the repression of trophoblast ferroptosis via the CREB/HO-1 pathway","authors":"Xiaojing Yue ,&nbsp;Menglan Pang ,&nbsp;Yun Chen,&nbsp;Zhixing Cheng,&nbsp;Ruisi Zhou,&nbsp;Yu Wang,&nbsp;Zhiqiang Zha,&nbsp;Liping Huang","doi":"10.1016/j.placenta.2024.10.013","DOIUrl":"10.1016/j.placenta.2024.10.013","url":null,"abstract":"<div><h3>Introduction</h3><div>Preeclampsia (PE) is a pregnancy-associated complication characterised by new-onset hypertension and proteinuria. This study explored the therapeutic potential of puerarin (Pue) in PE and investigated the underlying mechanism, with a focus on placental ferroptosis.</div></div><div><h3>Methods</h3><div>Using an N^G-nitro-L-arginine methyl ester (L-NAME)-induced PE mouse model, we assessed the effects of Pue on PE phenotypes and placental ferroptosis. Antioxidative and anti-ferroptotic effects of Pue were studied in three ferroptotic cell models (hypoxia/reperfusion, cobalt chloride, and erastin). The regulation of Pue on cAMP response element binding protein (CREB) and heme oxygenase-1 (HO-1) was evaluated through gain- and loss-of-function assays. Luciferase assays were used to elucidate the effect of Flag-CREB on <em>Hmox1</em> promoter fragments. CREB/HO-1 modulation by Pue was validated in mouse placentas with PE.</div></div><div><h3>Results</h3><div>Pue significantly alleviated maternal hypertension, proteinuria, fetal growth restriction, and placental damage in PE mice. This was associated with an upregulation of the anti-ferroptosis system (glutathione peroxidase 4 [GPX4], cys2/glutamate antiporter [SLC7A11], and glutathione [GSH]) and repression of reactive oxygen species (ROS) and malondialdehyde (MDA) in trophoblasts. Pue reduced HO-1 and CREB, and HO-1 deficiency upregulated GPX4 and SLC7A11. Manipulation of CREB expression led to changes in HO-1/GPX4; whereas, the regulation reversed by Pue administration. Flag-CREB enhanced luciferase activity on the full length <em>Hmox1</em> promoter (−2000/+78), which contains three CREB1 binding sites (S1–S3). In contrast, no increase in luciferase activity was observed with promoter fragments (−850/+78) and (−550/+78), which contain only the CREB1 binding sites S2 and S3, respectively.</div></div><div><h3>Discussion</h3><div>Pue ameliorated PE-like symptoms in mice by repressing trophoblast ferroptosis via inhibition of CREB signalling and affecting the <em>Homx1</em> promoter.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"158 ","pages":"Pages 145-155"},"PeriodicalIF":3.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142527700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}