Pub Date : 2024-11-01DOI: 10.1016/j.placenta.2024.03.006
Samantha G. Zambuto , Adrienne K. Scott , Michelle L. Oyen
This review considers fully three-dimensional biomaterial environments of varying complexity as these pertain to research on the placenta. The developments in placental cell sources are first considered, along with the corresponding maternal cells with which the trophoblast interact. We consider biomaterial sources, including hybrid and composite biomaterials. Properties and characterization of biomaterials are discussed in the context of material design for specific placental applications. The development of increasingly complicated three-dimensional structures includes examples of advanced fabrication methods such as microfluidic device fabrication and 3D bioprinting, as utilized in a placenta context. The review finishes with a discussion of the potential for in vitro, three-dimensional placenta research to address health disparities and sexual dimorphism, especially in light of the exciting recent changes in the regulatory environment for in vitro devices.
{"title":"Beyond 2D: Novel biomaterial approaches for modeling the placenta","authors":"Samantha G. Zambuto , Adrienne K. Scott , Michelle L. Oyen","doi":"10.1016/j.placenta.2024.03.006","DOIUrl":"10.1016/j.placenta.2024.03.006","url":null,"abstract":"<div><div><span>This review considers fully three-dimensional biomaterial environments of varying complexity as these pertain to research on the placenta. The developments in placental cell sources are first considered, along with the corresponding maternal cells with which the trophoblast interact. We consider biomaterial sources, including hybrid and composite biomaterials. Properties and characterization of biomaterials are discussed in the context of material design for specific placental applications. The development of increasingly complicated three-dimensional structures includes examples of advanced fabrication methods such as microfluidic device fabrication and 3D bioprinting, as utilized in a placenta context. The review finishes with a discussion of the potential for </span><em>in vitro</em><span>, three-dimensional placenta research to address health disparities and sexual dimorphism, especially in light of the exciting recent changes in the regulatory environment for </span><em>in vitro</em> devices.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"157 ","pages":"Pages 55-66"},"PeriodicalIF":3.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140181753","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}
Pub Date : 2024-10-30DOI: 10.1016/j.placenta.2024.10.067
Sanne D. van Otterdijk , Alexandra M. Binder , Karin B. Michels
Introduction
The neonates’ inflammatory response may in part be shaped during development by the placental epigenome, but evidence is scarce. We investigated the association between placental DNA methylation and pro-inflammatory proteins in cord blood.
Methods
A total of 249 mother-child dyads from the Harvard Epigenetic Birth Cohort were included in this study. Genome-wide methylation in placental DNA was assessed using the Illumina Human Methylation 450 Bead Chip array and verified by pyrosequencing. Cord blood inflammation markers assessed were interleukin-6, interleukin-8 and tumor necrosis factor α, intercellular adhesion molecule 1, serum amyloid A, and C-reactive protein.
Results
We identified differential placental DNA methylation of three loci in the HIVEP3 gene shore region that were associated with TNFα protein levels in cord blood. TNFα levels were associated with mode of delivery, gestational age and birth order. Three other loci located in the open sea region of the BCL11B gene were associated with SAA protein levels in cord blood. SAA levels were associated with birthweight, gestational age, and infant sex.
Conclusions
Our results suggest a potential role for HIVEP3 and BCL11B placental DNA methylation in the acute immune response of the neonate. These immune markers were correlated with several mother and child characteristics.
导言：新生儿的炎症反应可能部分是在发育过程中由胎盘表观基因组形成的，但这方面的证据还很少。我们研究了胎盘 DNA 甲基化与脐带血中促炎蛋白之间的关联：本研究共纳入了哈佛表观遗传出生队列中的 249 对母子。使用Illumina人类甲基化450珠芯片阵列评估胎盘DNA的全基因组甲基化，并通过热测序进行验证。评估的脐带血炎症标记物包括白细胞介素-6、白细胞介素-8和肿瘤坏死因子α、细胞间粘附分子1、血清淀粉样蛋白A和C反应蛋白：结果：我们发现HIVEP3基因岸区的三个位点的胎盘DNA甲基化差异与脐带血中的TNFα蛋白水平有关。TNFα水平与分娩方式、胎龄和胎次有关。位于BCL11B基因开放海区的另外三个位点与脐带血中的SAA蛋白水平有关。SAA水平与出生体重、胎龄和婴儿性别有关：我们的研究结果表明，HIVEP3 和 BCL11B 胎盘 DNA 甲基化在新生儿急性免疫反应中的潜在作用。这些免疫标记物与母婴的一些特征相关。
{"title":"Placental methylation and pro-inflammatory protein levels in cord blood","authors":"Sanne D. van Otterdijk , Alexandra M. Binder , Karin B. Michels","doi":"10.1016/j.placenta.2024.10.067","DOIUrl":"10.1016/j.placenta.2024.10.067","url":null,"abstract":"<div><h3>Introduction</h3><div>The neonates’ inflammatory response may in part be shaped during development by the placental epigenome, but evidence is scarce. We investigated the association between placental DNA methylation and pro-inflammatory proteins in cord blood.</div></div><div><h3>Methods</h3><div>A total of 249 mother-child dyads from the Harvard Epigenetic Birth Cohort were included in this study. Genome-wide methylation in placental DNA was assessed using the Illumina Human Methylation 450 Bead Chip array and verified by pyrosequencing. Cord blood inflammation markers assessed were interleukin-6, interleukin-8 and tumor necrosis factor α, intercellular adhesion molecule 1, serum amyloid A, and C-reactive protein.</div></div><div><h3>Results</h3><div>We identified differential placental DNA methylation of three loci in the <em>HIVEP3</em> gene shore region that were associated with TNFα protein levels in cord blood. TNFα levels were associated with mode of delivery, gestational age and birth order. Three other loci located in the open sea region of the <em>BCL11B</em> gene were associated with SAA protein levels in cord blood. SAA levels were associated with birthweight, gestational age, and infant sex.</div></div><div><h3>Conclusions</h3><div>Our results suggest a potential role for <em>HIVEP3</em> and <em>BCL11B</em> placental DNA methylation in the acute immune response of the neonate. These immune markers were correlated with several mother and child characteristics.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"158 ","pages":"Pages 231-239"},"PeriodicalIF":3.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605986","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}
Pub Date : 2024-10-29DOI: 10.1016/j.placenta.2024.10.023
Xiaoming Shi , Ling Jin , Xinlu Meng , Xiao Huo , Yan Sun , Lixiang Xue , Yuan Wei , Yuanyuan Wang , Zhongnan Yin , Yangyu Zhao , Lian Chen
Introduction
Placenta accreta spectrum (PAS) disorders pose a grave threat to maternal life due to severe hemorrhage and the heightened risk of peripartum hysterectomy. Consequently, there's a pressing need for circulating biomarkers in clinical settings. MicroRNAs (miRNAs), being stable in peripheral circulation, hold promise as potential biomarkers for PAS.
Methods
This study recruited singleton live pregnancies, including cases of invasive PAS, placenta previa (PP), and controls, across three phases. Initially, RNA-seq of peripheral blood identified 6 miRNAs in the screening phase. Subsequently, in the training and validation phases, miR-23a-5p, along with its target genes ASF1B and CHTF8, were validated using qRT-PCR. The diagnostic value of these markers for PAS and adverse outcomes was evaluated using Receiver Operating Characteristic (ROC) curves.
Results
The results showed miR-23a-5p was down-regulated in PAS, whereas ASF1B and CHTF8 were up-regulated. miR-23a-5p had modest diagnostic efficiency for PAS and adverse outcomes, as the AUC were 0.689 and 0.711 respectively. However, when miR-23a-5p combined with CHTF8, the AUC can improve greatly to 0.869 in PAS diagnosis and 0.856 in prediction of adverse outcomes.
Discussion
We propose the miR-23a-5p plays a role in PAS pathogenesis through regulating cell proliferation, migration, invasion, apoptosis by targeting various genes. This study confirmed its potential value of miR-23a-5p combined with target gene CHTF8 as novel biomarkers for PAS and adverse outcomes.
{"title":"Transcriptomic analysis identified novel biomarker in invasive placenta accreta spectrum","authors":"Xiaoming Shi , Ling Jin , Xinlu Meng , Xiao Huo , Yan Sun , Lixiang Xue , Yuan Wei , Yuanyuan Wang , Zhongnan Yin , Yangyu Zhao , Lian Chen","doi":"10.1016/j.placenta.2024.10.023","DOIUrl":"10.1016/j.placenta.2024.10.023","url":null,"abstract":"<div><h3>Introduction</h3><div>Placenta accreta spectrum (PAS) disorders pose a grave threat to maternal life due to severe hemorrhage and the heightened risk of peripartum hysterectomy. Consequently, there's a pressing need for circulating biomarkers in clinical settings. MicroRNAs (miRNAs), being stable in peripheral circulation, hold promise as potential biomarkers for PAS.</div></div><div><h3>Methods</h3><div>This study recruited singleton live pregnancies, including cases of invasive PAS, placenta previa (PP), and controls, across three phases. Initially, RNA-seq of peripheral blood identified 6 miRNAs in the screening phase. Subsequently, in the training and validation phases, miR-23a-5p, along with its target genes ASF1B and CHTF8, were validated using qRT-PCR. The diagnostic value of these markers for PAS and adverse outcomes was evaluated using Receiver Operating Characteristic (ROC) curves.</div></div><div><h3>Results</h3><div>The results showed miR-23a-5p was down-regulated in PAS, whereas ASF1B and CHTF8 were up-regulated. miR-23a-5p had modest diagnostic efficiency for PAS and adverse outcomes, as the AUC were 0.689 and 0.711 respectively. However, when miR-23a-5p combined with CHTF8, the AUC can improve greatly to 0.869 in PAS diagnosis and 0.856 in prediction of adverse outcomes.</div></div><div><h3>Discussion</h3><div>We propose the miR-23a-5p plays a role in PAS pathogenesis through regulating cell proliferation, migration, invasion, apoptosis by targeting various genes. This study confirmed its potential value of miR-23a-5p combined with target gene CHTF8 as novel biomarkers for PAS and adverse outcomes.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"158 ","pages":"Pages 301-309"},"PeriodicalIF":3.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644401","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}
Pub Date : 2024-10-28DOI: 10.1016/j.placenta.2024.10.020
Nikhilesh Bappoo , Yutthapong Tongpob , Matina Hakim , Jenny Myers , Emma Panting , Karen E. Chapman , Adrian J.W. Thomson , Carmel M. Moran , Lachlan J. Kelsey , Vijayalakshmi Srinivasan , Joanna L. James , Alys R. Clark , Barry J. Doyle , Caitlin S. Wyrwoll
Introduction
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.
Methods
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.
Results
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.
Discussion
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.
{"title":"Feto-placental vascular structure and in silico haemodynamics: Of mice, rats, and human","authors":"Nikhilesh Bappoo , Yutthapong Tongpob , Matina Hakim , Jenny Myers , Emma Panting , Karen E. Chapman , Adrian J.W. Thomson , Carmel M. Moran , Lachlan J. Kelsey , Vijayalakshmi Srinivasan , Joanna L. James , Alys R. Clark , Barry J. Doyle , 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}
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.
Methods
This study examines the methylation and expression profile of imprinted genes - PEG10, PEG3, MEST, and DLK1 in circulating EVs of 1st and 3rd trimester control and early onset preeclampsia (EOPE) pregnant women (n = 15) using pyrosequencing and qRT-PCR respectively.
Results
In 1st trimester, PEG3 was significantly hypermethylated, whereas no significant methylation changes were noted in PEG10 and MEST in EOPE. In 3rd trimester, significant hypomethylation in PEG10, PEG3 and IGDMR was observed whereas significant hypermethyaltion noted in MEST. mRNA expression of PEG10, PEG3 and DLK1 was not affected in circulating EVs of 1st trimester EOPE. However, in 3rd trimester significant increased expression in PEG10, PEG3 and DLK1 noted. MEST expression was reduced in 3rd trimester EOPE. No correlation was observed between average DNA methylation and gene expression in PEG10 and PEG3 in 1st trimester. However, in 3rd trimester, significant negative correlation was noted in PEG10 (r = −0.426, p = 0.04), PEG3 (r = −0.496, p = 0.01), MEST (r = −0.398, p = 0.03) and DLK1 (r = −0.403, p = 0.03).
Discussion
The results of our study strengthen the potential of circulating EVs from maternal serum as non-invasive indicators of placental pathophysiology, including preeclampsia.
导言子痫前期（PE）是一种以高血压为特征的妊娠并发症，对母体和胎儿的健康构成威胁。"基因组印记 "是一种由不同甲基化区域（DMR）的 DNA 甲基化调控的表观遗传现象，影响着胎盘的发育。对 PE 中循环细胞外囊泡（EVs）的研究表明，它们是早期生物标志物的潜在来源，但子痫前期 EV-DNA 的甲基化状态尚未见报道：本研究采用热测序法和 qRT-PCR 法分别检测了第一和第三孕期对照组和早发子痫前期（EOPE）孕妇（n = 15）循环 EV 中印记基因 PEG10、PEG3、MEST 和 DLK1 的甲基化和表达谱：结果：在妊娠头三个月，PEG3 发生了明显的高甲基化，而在 EOPE 中，PEG10 和 MEST 没有发生明显的甲基化变化。在妊娠三个月时，PEG10、PEG3 和 IGDMR 发生了明显的低甲基化，而 MEST 则发生了明显的高甲基化。在妊娠三个月的 EOPE 循环 EV 中，PEG10、PEG3 和 DLK1 的 mRNA 表达未受影响。然而，在怀孕三个月时，PEG10、PEG3 和 DLK1 的表达明显增加。在妊娠三个月的 EOPE 中，MEST 的表达减少。在妊娠头三个月，PEG10 和 PEG3 的平均 DNA 甲基化与基因表达之间没有相关性。然而，在妊娠第 3 个月，PEG10（r = -0.426，p = 0.04）、PEG3（r = -0.496，p = 0.01）、MEST（r = -0.398，p = 0.03）和 DLK1（r = -0.403，p = 0.03）的基因表达呈显著负相关：讨论：我们的研究结果增强了母体血清中的循环EV作为胎盘病理生理学（包括子痫前期）非侵入性指标的潜力。
{"title":"Methylation and expression of imprinted genes in circulating extracellular vesicles from women experiencing early onset preeclampsia","authors":"Uma Shinde , Kushaan Khambata , Sanketa Raut , Aishwarya Rao , Vandana Bansal , Niranjan Mayadeo , Dhanjit kumar Das , Taruna Madan , Vinoth Prasanna Gunasekaran , 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<sup>st</sup> and 3<sup>rd</sup> 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<sup>st</sup> 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<sup>rd</sup> 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<sup>st</sup> trimester EOPE. However, in 3<sup>rd</sup> trimester significant increased expression in <em>PEG10</em>, <em>PEG3</em> and <em>DLK1</em> noted. <em>MEST</em> expression was reduced in 3<sup>rd</sup> trimester EOPE. No correlation was observed between average DNA methylation and gene expression in <em>PEG10</em> and <em>PEG3</em> in 1<sup>st</sup> trimester. However, in 3<sup>rd</sup> 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}
Pub Date : 2024-10-24DOI: 10.1016/j.placenta.2024.10.021
K.L. Milan , V. Gayatri , Kumaran Kriya , N. Sanjushree , Sri Vishwanathan Palanivel , M. Anuradha , Kunka Mohanram Ramkumar
Introduction
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.
Methods
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.
Results
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.
Discussion
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.
{"title":"MiR-142-5p mediated Nrf2 dysregulation in gestational diabetes mellitus and its impact on placental angiogenesis","authors":"K.L. Milan , V. Gayatri , Kumaran Kriya , N. Sanjushree , Sri Vishwanathan Palanivel , M. Anuradha , 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}
Pub Date : 2024-10-24DOI: 10.1016/j.placenta.2024.10.022
Helene Fjeldvik Peterson , Kari Flo , Silje Sommerfelt , Vigdis Hillestad
Objectives
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.
Methods
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.
Results
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 < 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 < 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.
Conclusions
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.
{"title":"Placental volume at gestational week 27 and subsequent fetal growth: An observational study","authors":"Helene Fjeldvik Peterson , Kari Flo , Silje Sommerfelt , 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 < 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 < 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) cm<sup>3</sup>/day versus 25 (SD 3) cm<sup>3</sup>/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}
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.
Material and methods
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.
Results
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).
Conclusion
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.
{"title":"Placenta-associated biomarkers and pregnancy outcome in HPA-1a alloimmunization: A prospective cohort study","authors":"Nora Hersoug Nedberg , Mona Nystad , Maria Therese Ahlen , Eirin Listau Bertelsen , Katarzyna Guz , Małgorzata Uhrynowska , Marzena Dębska , Agnieszka Gierszon , Agnieszka Orzińska , Anne Husebekk , Ewa Brojer , Anne Cathrine Staff , 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}
Pub Date : 2024-10-24DOI: 10.1016/j.placenta.2024.10.011
Hongyu Su , Min Li , Na Li , Yingying Zhang , Yun He , Ze Zhang , Yumeng Zhang , Qinqin Gao , Zhice Xu , Jiaqi Tang
Background
Placenta plays a vital role in preeclampsia. The present study investigated the role of endothelin-1 (ET-1) and its receptors in preeclampsia placenta.
Method
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.
Results
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. In utero 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.
Conclusion
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. In utero 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.
{"title":"Endothelin-1 potentiated constriction in preeclampsia placental veins: Role of ETAR/ETBR/CaV1.2/CALD1","authors":"Hongyu Su , Min Li , Na Li , Yingying Zhang , Yun He , Ze Zhang , Yumeng Zhang , Qinqin Gao , Zhice Xu , 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}
Pub Date : 2024-10-23DOI: 10.1016/j.placenta.2024.10.018
Chen Wang, Minghui Liu, Jie Yan, Jie Ning, Shuxian Wang, Huixia Yang
Objective
We aimed to explore whether maternal exercise has epigenetic effects on improving the adverse placental environment associated with maternal overweight/obesity.
Methods
Based on samples collected from an RCT cohort, differentially methylated genes and expressed protein-coding RNA were identified in the placentas of 16 women with overweight and obesity who did or did not participate in an exercise intervention using the Infinium HumanMethylation850 BeadChip array and RNA Sequencing-Based lncRNA Profiling. Potential target genes were further identified by integrating this information. Then, the target genes' methylation and expression levels were verified, and correlation analysis was performed with placental oxidative stress markers and participants’ clinical metabolic parameters.
Results
A total of 3608 significant differentially methylated probes were detected. The CBR1 gene, which was previously identified as a possible antioxidant, was significantly hypomethylated at CPG site promoter regions in placentas from the exercise group, and CBR1 gene expression levels were significantly higher. CBR1 gene expression levels were negatively associated with DNA methylation levels. Furthermore, CBR1 gene expression levels were negatively correlated with MDA levels in both placenta and cord blood samples and insulin resistance levels in late pregnancy. Additionally, CBR1 methylation levels were positively correlated with fasting plasma glucose and insulin resistance levels in late pregnancy.
Conclusion
DNA methylation is involved in the ameliorating effect of exercise on the adverse placental environment associated with maternal overweight/obesity.
{"title":"Epigenetic effects of exercise on improving the adverse placental environment associated with maternal overweight and obesity","authors":"Chen Wang, Minghui Liu, Jie Yan, Jie Ning, Shuxian Wang, Huixia Yang","doi":"10.1016/j.placenta.2024.10.018","DOIUrl":"10.1016/j.placenta.2024.10.018","url":null,"abstract":"<div><h3>Objective</h3><div>We aimed to explore whether maternal exercise has epigenetic effects on improving the adverse placental environment associated with maternal overweight/obesity.</div></div><div><h3>Methods</h3><div>Based on samples collected from an RCT cohort, differentially methylated genes and expressed protein-coding RNA were identified in the placentas of 16 women with overweight and obesity who did or did not participate in an exercise intervention using the Infinium HumanMethylation850 BeadChip array and RNA Sequencing-Based lncRNA Profiling. Potential target genes were further identified by integrating this information. Then, the target genes' methylation and expression levels were verified, and correlation analysis was performed with placental oxidative stress markers and participants’ clinical metabolic parameters.</div></div><div><h3>Results</h3><div>A total of 3608 significant differentially methylated probes were detected. The CBR1 gene, which was previously identified as a possible antioxidant, was significantly hypomethylated at CPG site promoter regions in placentas from the exercise group, and CBR1 gene expression levels were significantly higher. CBR1 gene expression levels were negatively associated with DNA methylation levels. Furthermore, CBR1 gene expression levels were negatively correlated with MDA levels in both placenta and cord blood samples and insulin resistance levels in late pregnancy. Additionally, CBR1 methylation levels were positively correlated with fasting plasma glucose and insulin resistance levels in late pregnancy.</div></div><div><h3>Conclusion</h3><div>DNA methylation is involved in the ameliorating effect of exercise on the adverse placental environment associated with maternal overweight/obesity.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"158 ","pages":"Pages 329-337"},"PeriodicalIF":3.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695605","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}
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