Placenta最新文献_第2页

HIF-2α / HILPDA promotes ferroptosis sensitivity in placenta trophoblast cells of early-onset preeclampsia HIF-2α / HILPDA促进早发性子痫前期胎盘滋养细胞对铁下垂的敏感性。

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-12-15 DOI: 10.1016/j.placenta.2025.12.009

Qianghua Wang , Nana Yang , Huijuan Chen , Biao Ding , Chengli Dou , Xuegu Wang , Xingchen Pan , Xiaojing Wang , Xiang Li

Background

Early-onset preeclampsia (EOPE) is a severe pregnancy disorder characterized by placental dysfunction. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a key pathogenic mechanism in EOPE. This study investigated the role of the hypoxia-inducible factor-2α (HIF-2α) and its downstream target, Hypoxia-Inducible Lipid Droplet-Associated protein (HILPDA), in regulating ferroptosis in EOPE placentas.

Methods

Placental tissues from EOPE patients and normotensive controls were analyzed for ferroptosis markers (MDA, GSH, ACSL4, Ferroportin-1, GPX4) and HILPDA/HIF-2α expression. In vitro models employed HTR-8/SVneo trophoblasts and primary human trophoblasts. HILPDA was manipulated via siRNA knockdown or CRISPR-Cas9 knockout. HIF-2α was pharmacologically activated using agonists (HIF-2α agonist 2, AKB-6899). Erastin was used to induce ferroptosis. Assessments included CCK-8 assays for viability, C11-BODIPY581/591 staining and flow cytometry for lipid peroxidation, MDA/GSH quantification for ferroptosis levels, qRT-PCR and Western blotting for HILPDA/HIF-α expression.

Results

EOPE placentas exhibited significantly elevated ferroptosis, with increased MDA, ACSL4, Ferroportin-1; decreased GSH, GPX4, and upregulated expression of both HILPDA and HIF-2α (but not HIF-1α) compared to controls. In vitro, HIF-2α activation triggered HILPDA expression and robust ferroptosis (increased lipid peroxidation, MDA; decreased GSH; reduced viability) in trophoblasts. Crucially, HILPDA knockdown/knockout significantly attenuated ferroptosis sensitivity and protected trophoblast viability against both Erastin and HIF-2α agonist-induced ferroptotic stress. HIF-2α-induced ferroptosis was substantially rescued by HILPDA deficiency.

Conclusion

Our findings identify the HIF-2α/HILPDA axis as a critical regulator of trophoblast ferroptosis in EOPE. HIF-2α, upregulated in EOPE placenta, transcriptionally induces HILPDA, which sensitizes trophoblasts to ferroptotic death. Targeting this signaling pathway represents a promising therapeutic strategy for mitigating placental dysfunction in EOPE.

背景：早发型子痫前期（EOPE）是一种以胎盘功能障碍为特征的严重妊娠疾病。铁死亡是一种铁依赖性的细胞死亡形式，已成为EOPE的一个关键致病机制。本研究探讨了缺氧诱导因子-2α (HIF-2α)及其下游靶点低氧诱导脂滴相关蛋白（HILPDA）在EOPE胎盘铁下垂中的调节作用。方法：分析EOPE患者和正常对照组胎盘组织中铁下垂标志物（MDA、GSH、ACSL4、Ferroportin-1、GPX4）和HILPDA/HIF-2α的表达。体外模型采用HTR-8/SVneo滋养细胞和人原代滋养细胞。通过siRNA敲低或CRISPR-Cas9敲除来操纵HILPDA。HIF-2α使用激动剂（HIF-2α激动剂2，AKB-6899）进行药理学激活。用Erastin诱导铁下垂。评估包括CCK-8活力测定，C11-BODIPY581/591染色和流式细胞术检测脂质过氧化，MDA/GSH定量检测铁沉水平，qRT-PCR和Western blotting检测HILPDA/HIF-α表达。结果：EOPE胎盘表现出明显的铁下垂，MDA、ACSL4、铁转运蛋白-1升高；与对照组相比，GSH、GPX4降低，HILPDA和HIF-2α表达上调（但HIF-1α不上调）。在体外，HIF-2α激活触发了滋养细胞HILPDA的表达和强大的铁下垂（脂质过氧化，MDA增加，GSH降低，活力降低）。至关重要的是，HILPDA敲除/敲除显著降低了铁致凋亡的敏感性，并保护了滋养细胞对Erastin和HIF-2α激动剂诱导的铁致凋亡应激的活性。hif -2α-诱导的铁下垂在HILPDA缺乏的情况下基本恢复。结论：我们的研究结果表明HIF-2α/HILPDA轴是EOPE中滋养细胞铁下垂的关键调节因子。HIF-2α在EOPE胎盘中上调，转录诱导HILPDA，使滋养细胞致铁性死亡。靶向这一信号通路是缓解EOPE患者胎盘功能障碍的一种有希望的治疗策略。

{"title":"HIF-2α / HILPDA promotes ferroptosis sensitivity in placenta trophoblast cells of early-onset preeclampsia","authors":"Qianghua Wang , Nana Yang , Huijuan Chen , Biao Ding , Chengli Dou , Xuegu Wang , Xingchen Pan , Xiaojing Wang , Xiang Li","doi":"10.1016/j.placenta.2025.12.009","DOIUrl":"10.1016/j.placenta.2025.12.009","url":null,"abstract":"<div><h3>Background</h3><div>Early-onset preeclampsia (EOPE) is a severe pregnancy disorder characterized by placental dysfunction. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a key pathogenic mechanism in EOPE. This study investigated the role of the hypoxia-inducible factor-2α (HIF-2α) and its downstream target, Hypoxia-Inducible Lipid Droplet-Associated protein (HILPDA), in regulating ferroptosis in EOPE placentas.</div></div><div><h3>Methods</h3><div>Placental tissues from EOPE patients and normotensive controls were analyzed for ferroptosis markers (MDA, GSH, ACSL4, Ferroportin-1, GPX4) and HILPDA/HIF-2α expression. In vitro models employed HTR-8/SVneo trophoblasts and primary human trophoblasts. HILPDA was manipulated via siRNA knockdown or CRISPR-Cas9 knockout. HIF-2α was pharmacologically activated using agonists (HIF-2α agonist 2, AKB-6899). Erastin was used to induce ferroptosis. Assessments included CCK-8 assays for viability, C11-BODIPY581/591 staining and flow cytometry for lipid peroxidation, MDA/GSH quantification for ferroptosis levels, qRT-PCR and Western blotting for HILPDA/HIF-α expression.</div></div><div><h3>Results</h3><div>EOPE placentas exhibited significantly elevated ferroptosis, with increased MDA, ACSL4, Ferroportin-1; decreased GSH, GPX4, and upregulated expression of both HILPDA and HIF-2α (but not HIF-1α) compared to controls. In vitro, HIF-2α activation triggered HILPDA expression and robust ferroptosis (increased lipid peroxidation, MDA; decreased GSH; reduced viability) in trophoblasts. Crucially, HILPDA knockdown/knockout significantly attenuated ferroptosis sensitivity and protected trophoblast viability against both Erastin and HIF-2α agonist-induced ferroptotic stress. HIF-2α-induced ferroptosis was substantially rescued by HILPDA deficiency.</div></div><div><h3>Conclusion</h3><div>Our findings identify the HIF-2α/HILPDA axis as a critical regulator of trophoblast ferroptosis in EOPE. HIF-2α, upregulated in EOPE placenta, transcriptionally induces HILPDA, which sensitizes trophoblasts to ferroptotic death. Targeting this signaling pathway represents a promising therapeutic strategy for mitigating placental dysfunction in EOPE.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 126-137"},"PeriodicalIF":2.5,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805289","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}

引用次数: 0

NLRP3 inflammasome activation in the placenta during SARS-CoV-2 infection SARS-CoV-2感染期间胎盘中NLRP3炎性体的激活

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-12-14 DOI: 10.1016/j.placenta.2025.12.007

Ana María Arboleda-Borrero , Eliécer Jiménez-Charris , Laura Andrea Gómez , Wilmar Saldarriaga , Javier Fonseca , Mildrey Mosquera Escudero

Background

The NLRP3 inflammasome is a key regulator of innate immunity. Its overactivation contributes to cytokine release and tissue inflammation during SARS-CoV-2 infection. However, its role in placental inflammation and pregnancy outcomes remains unclear.

Objective

To evaluate whether SARS-CoV-2 infection during pregnancy induces NLRP3 inflammasome activation in placental tissue and to assess its association with maternal and neonatal outcomes.

Methods

A prospective cohort study included 25 pregnant women with RT-PCR–confirmed COVID-19 and 25 healthy controls. Placental NLRP3, Caspase-1, IL-1β, and IL-18 expression were analyzed by qRT-PCR and Western blotting. Maternal and cord plasma cytokines were quantified by ELISA and cytometric bead array. Viral RNA, antibody transfer, and nutrient transporter gene expression were also evaluated.

Results

Placentas from infected women showed higher NLRP3 (p = 0.015) and Caspase-1 (p = 0.029) mRNA levels compared with controls. Western blotting detected procaspase-1 (∼50 kDa) and cleaved caspase-1 (∼35 kDa), indicating inflammasome activation. Maternal IL-18 concentrations were elevated (p = 0.013), while IL-1β remained unchanged. SARS-CoV-2 RNA was identified in 8 % of placentas (variants 21H and 20A). IgG antibodies were found in 28 % of maternal and 24 % of cord samples (p = 0.017). Infected pregnancies showed lower gestational age at delivery (p = 0.023), higher cesarean rate (p = 0.004), and lower neonatal Apgar scores (p = 0.006, p = 0.015). Nutrient transporter expression was preserved.

Conclusion

SARS-CoV-2 infection during pregnancy induces activation of the NLRP3 inflammasome in placental tissue and systemic elevation of IL-18, indicating both local and systemic inflammation.

背景：NLRP3炎性小体是先天免疫的关键调节因子。在SARS-CoV-2感染期间，其过度激活有助于细胞因子释放和组织炎症。然而，其在胎盘炎症和妊娠结局中的作用尚不清楚。目的：探讨妊娠期SARS-CoV-2感染是否会诱导胎盘组织NLRP3炎性体激活，并评估其与孕产妇和新生儿预后的关系。方法：前瞻性队列研究包括25名经rt - pcr确诊的COVID-19孕妇和25名健康对照。采用qRT-PCR和Western blotting检测胎盘NLRP3、Caspase-1、IL-1β和IL-18的表达。采用酶联免疫吸附法和流式细胞仪测定母血和脐带血浆细胞因子。病毒RNA、抗体转移和营养转运蛋白基因表达也被评估。结果：与对照组相比，感染妇女胎盘NLRP3 （p = 0.015）和Caspase-1 (p = 0.029) mRNA水平较高。Western blotting检测到procaspase-1 （~ 50 kDa）和cleaved caspase-1 (~ 35 kDa)，表明炎性小体激活。母体IL-18浓度升高（p = 0.013），而IL-1β保持不变。在8%的胎盘（变体21H和20A）中鉴定出SARS-CoV-2 RNA。在28%的母体和24%的脐带样本中发现IgG抗体（p = 0.017）。感染孕妇分娩时胎龄较低（p = 0.023），剖宫产率较高（p = 0.004），新生儿Apgar评分较低（p = 0.006, p = 0.015）。保留了营养转运蛋白的表达。结论：妊娠期SARS-CoV-2感染可诱导胎盘组织NLRP3炎性小体激活和IL-18全身性升高，提示有局部和全身性炎症。

{"title":"NLRP3 inflammasome activation in the placenta during SARS-CoV-2 infection","authors":"Ana María Arboleda-Borrero , Eliécer Jiménez-Charris , Laura Andrea Gómez , Wilmar Saldarriaga , Javier Fonseca , Mildrey Mosquera Escudero","doi":"10.1016/j.placenta.2025.12.007","DOIUrl":"10.1016/j.placenta.2025.12.007","url":null,"abstract":"<div><h3>Background</h3><div>The NLRP3 inflammasome is a key regulator of innate immunity. Its overactivation contributes to cytokine release and tissue inflammation during SARS-CoV-2 infection. However, its role in placental inflammation and pregnancy outcomes remains unclear.</div></div><div><h3>Objective</h3><div>To evaluate whether SARS-CoV-2 infection during pregnancy induces NLRP3 inflammasome activation in placental tissue and to assess its association with maternal and neonatal outcomes.</div></div><div><h3>Methods</h3><div>A prospective cohort study included 25 pregnant women with RT-PCR–confirmed COVID-19 and 25 healthy controls. Placental <em>NLRP3</em>, <em>Caspase-1</em>, <em>IL-1β</em>, and <em>IL-18</em> expression were analyzed by qRT-PCR and Western blotting. Maternal and cord plasma cytokines were quantified by ELISA and cytometric bead array. Viral RNA, antibody transfer, and nutrient transporter gene expression were also evaluated.</div></div><div><h3>Results</h3><div>Placentas from infected women showed higher <em>NLRP3</em> (p = 0.015) and <em>Caspase-1</em> (p = 0.029) mRNA levels compared with controls. Western blotting detected procaspase-1 (∼50 kDa) and cleaved caspase-1 (∼35 kDa), indicating inflammasome activation. Maternal IL-18 concentrations were elevated (p = 0.013), while IL-1β remained unchanged. SARS-CoV-2 RNA was identified in 8 % of placentas (variants 21H and 20A). IgG antibodies were found in 28 % of maternal and 24 % of cord samples (p = 0.017). Infected pregnancies showed lower gestational age at delivery (p = 0.023), higher cesarean rate (p = 0.004), and lower neonatal Apgar scores (p = 0.006, p = 0.015). Nutrient transporter expression was preserved.</div></div><div><h3>Conclusion</h3><div>SARS-CoV-2 infection during pregnancy induces activation of the NLRP3 inflammasome in placental tissue and systemic elevation of IL-18, indicating both local and systemic inflammation.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 117-125"},"PeriodicalIF":2.5,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794621","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}

引用次数: 0

Retraction notice to “Circ_0085296 suppresses trophoblast cell proliferation, invasion, and migration via modulating miR-144/E-cadherin axis” [Geriatric Nursing 97 (2020) 18–25] “Circ_0085296通过调节miR-144/E-cadherin轴抑制滋养细胞增殖、侵袭和迁移”的撤回通知[老年护理97 (2020)18-25]

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-12-12 DOI: 10.1016/j.placenta.2025.12.004

Hailing Zhu , Xia Niu , Qinghua Li , Yuehua Zhao , Xue Chen , Hesheng Sun

引用次数: 0

Placental vascular remodeling in preeclampsia: A three-dimensional analysis of microvascular alterations across disease severity 子痫前期胎盘血管重构：疾病严重程度的微血管改变的三维分析

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-12-11 DOI: 10.1016/j.placenta.2025.12.005

Mingqun Li , Xiaoqiang Han , Yao Peng , Yang He , Qiangqiang You , Jiaqi Zhang

Introduction

This study aimed to characterize placental vascular morphological alterations across different severities of preeclampsia (PE) using advanced three-dimensional (3D) imaging and histological techniques, exploring correlations between placental microvascular changes and disease severity.

Methods

A prospective observational study included 122 singleton pregnancies, categorized as normal (n = 45), mild PE (n = 51), or severe PE (n = 26). Placental vascular casts were created through modified resin casting, followed by 3D computed tomography (CT) reconstruction, scanning electron microscopy (SEM), and histopathological analysis. Vascular morphometry, volume, density, and microstructural features were quantitatively assessed.

Results

Significant intergroup differences in placental vascular characteristics were identified. Compared with normal placentas, mild PE exhibited compensatory increases in total vascular volume, primarily due to venous expansion, while severe PE demonstrated significantly reduced vascular volumes and grades (P < 0.01). Morphometric analysis indicated progressive narrowing of distal venous (V3–V5: 24.9–32.5 %) and arterial branches (A3–A4: 19.7–23.2 %) correlating with PE severity. Vascular density analysis showed a marked stepwise reduction from normal to severe PE groups, with venous networks being most affected (31.1 % decrease, P < 0.001). SEM and histopathological examinations confirmed severe vascular rarefaction, abnormal vessel morphology, and hallmark pathological changes in severe PE. Further correlation analysis demonstrated that total placental vascular density was positively associated with neonatal birth weight (ρ = 0.523, P < 0.001), MCA peak systolic velocity (ρ = 0.218, P = 0.042), and 1-min Apgar score (ρ = 0.344, P = 0.005), while showing significant negative correlations with umbilical artery PI (ρ = −0.387, P = 0.003), NICU admission (ρ = −0.297, P = 0.011), maternal serum creatinine (ρ = −0.262, P = 0.027), and maternal ALT levels (ρ = −0.233, P = 0.038).

Discussion

Placental microvascular alterations correlate significantly with preeclampsia severity. Our findings highlight distinct vascular remodeling patterns in PE and provide essential morphological evidence supporting microcirculatory dysfunction as a key pathological mechanism in preeclampsia progression.

本研究旨在利用先进的三维（3D）成像和组织学技术表征不同程度子痫前期（PE）胎盘血管形态学改变，探索胎盘微血管变化与疾病严重程度之间的相关性。方法：一项前瞻性观察研究纳入122例单胎妊娠，分为正常妊娠（n = 45）、轻度妊娠（n = 51）和重度妊娠（n = 26）。采用改良树脂浇铸制备胎盘血管模型，然后进行三维计算机断层扫描（CT）重建、扫描电镜（SEM）和组织病理学分析。定量评估血管形态、体积、密度和微观结构特征。结果：胎盘血管特征组间差异显著。与正常胎盘相比，轻度PE表现出总血管容量代偿性增加，主要是由于静脉扩张，而严重PE表现出血管体积和等级显著降低(P讨论：胎盘微血管改变与子痫前期严重程度显著相关。我们的研究结果强调了PE中不同的血管重塑模式，并提供了必要的形态学证据，支持微循环功能障碍是子痫前期进展的关键病理机制。

{"title":"Placental vascular remodeling in preeclampsia: A three-dimensional analysis of microvascular alterations across disease severity","authors":"Mingqun Li , Xiaoqiang Han , Yao Peng , Yang He , Qiangqiang You , Jiaqi Zhang","doi":"10.1016/j.placenta.2025.12.005","DOIUrl":"10.1016/j.placenta.2025.12.005","url":null,"abstract":"<div><h3>Introduction</h3><div>This study aimed to characterize placental vascular morphological alterations across different severities of preeclampsia (PE) using advanced three-dimensional (3D) imaging and histological techniques, exploring correlations between placental microvascular changes and disease severity.</div></div><div><h3>Methods</h3><div>A prospective observational study included 122 singleton pregnancies, categorized as normal (n = 45), mild PE (n = 51), or severe PE (n = 26). Placental vascular casts were created through modified resin casting, followed by 3D computed tomography (CT) reconstruction, scanning electron microscopy (SEM), and histopathological analysis. Vascular morphometry, volume, density, and microstructural features were quantitatively assessed.</div></div><div><h3>Results</h3><div>Significant intergroup differences in placental vascular characteristics were identified. Compared with normal placentas, mild PE exhibited compensatory increases in total vascular volume, primarily due to venous expansion, while severe PE demonstrated significantly reduced vascular volumes and grades (<em>P</em> < 0.01). Morphometric analysis indicated progressive narrowing of distal venous (V3–V5: 24.9–32.5 %) and arterial branches (A3–A4: 19.7–23.2 %) correlating with PE severity. Vascular density analysis showed a marked stepwise reduction from normal to severe PE groups, with venous networks being most affected (31.1 % decrease, <em>P</em> < 0.001). SEM and histopathological examinations confirmed severe vascular rarefaction, abnormal vessel morphology, and hallmark pathological changes in severe PE. Further correlation analysis demonstrated that total placental vascular density was positively associated with neonatal birth weight (ρ = 0.523, <em>P</em> < 0.001), MCA peak systolic velocity (ρ = 0.218, <em>P</em> = 0.042), and 1-min Apgar score (ρ = 0.344, <em>P</em> = 0.005), while showing significant negative correlations with umbilical artery PI (ρ = −0.387, P = 0.003), NICU admission (ρ = −0.297, <em>P</em> = 0.011), maternal serum creatinine (ρ = −0.262, <em>P</em> = 0.027), and maternal ALT levels (ρ = −0.233, <em>P</em> = 0.038).</div></div><div><h3>Discussion</h3><div>Placental microvascular alterations correlate significantly with preeclampsia severity. Our findings highlight distinct vascular remodeling patterns in PE and provide essential morphological evidence supporting microcirculatory dysfunction as a key pathological mechanism in preeclampsia progression.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 96-108"},"PeriodicalIF":2.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757231","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}

引用次数: 0

Cell-free DNA methylation profiling in early-onset preeclampsia using methylated DNA sequencing 使用甲基化DNA测序分析早发性子痫前期的无细胞DNA甲基化谱

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-12-11 DOI: 10.1016/j.placenta.2025.12.006

M.M. van Vliet , R.G. Boers , R.J.H. Galjaard , J.B. Boers , R.P.M. Steegers-Theunissen , J. Gribnau , S. Schoenmakers

Introduction

Distinct DNA methylation profiles have been identified in maternal plasma cell-free DNA (cfDNA) in early-onset preeclampsia (EOPE). However, findings across studies often lack concordance and the biological mechanisms driving methylation differences are largely unknown. We aimed to identify EOPE-associated differentially methylated regions (DMRs), investigate changes in tissue-specific cfDNA contributions and validate previously reported EOPE-associated regions.

Methods

First-trimester cfDNA (n = 35) and cfDNA after diagnosis (n = 21) were collected from EOPE pregnancies and matched-controls. Placental tissues were collected from EOPE (n = 5) and control (n = 7) pregnancies. MeD-seq assays were performed to identify DMRs. Placental-contribution to cfDNA, cfDNA concentration, EOPE-specific placental markers, and methylation levels at previously identified EOPE-associated regions were compared between cases and controls. Additionally, liver-, kidney-, and endothelium-specific hypermethylated regions were identified using publicly available datasets and compared in cfDNA.

Results

We identified one DMR in the first trimester and 249 DMRs in our after diagnosis cohort. Total cfDNA concentration was 20-fold higher after EOPE diagnosis compared to controls (p < 0.001). We identified 606 DMRs in EOPE placentas, which unexpectedly were almost not present in cfDNA after EOPE diagnosis. Also, the placental-, liver-, and kidney-specific contributions were relatively decreased, while endothelium-specific methylation was increased. Only 2.7–8.4 % of previously identified regions showed significant differential methylation in our cohort.

Discussion

Differential tissue contributions to cfDNA likely account for DMRs identified after EOPE diagnosis. Further research is required to clarify the (tissue) origins of identified cfDNA DMRs in more detail. Lack of concordance across studies remains a significant limitation, potentially explained by methodological heterogeneity.

在早发性子痫前期（EOPE）的母体血浆无细胞DNA （cfDNA）中发现了不同的DNA甲基化谱。然而，研究结果往往缺乏一致性，驱动甲基化差异的生物学机制在很大程度上是未知的。我们的目的是确定eope相关的差异甲基化区域（DMRs），研究组织特异性cfDNA贡献的变化，并验证先前报道的eope相关区域。方法收集EOPE妊娠早期cfDNA（35例）和诊断后cfDNA（21例）及配对对照。收集EOPE妊娠（n = 5）和对照组（n = 7）的胎盘组织。采用MeD-seq法鉴定DMRs。在病例和对照组之间比较了胎盘对cfDNA的贡献、cfDNA浓度、eope特异性胎盘标志物和先前确定的eope相关区域的甲基化水平。此外，使用公开可用的数据集鉴定肝脏、肾脏和内皮特异性高甲基化区域，并在cfDNA中进行比较。结果我们在妊娠早期发现1例DMR，在诊断后的队列中发现249例DMR。诊断为EOPE后总cfDNA浓度比对照组高20倍（p < 0.001）。我们在EOPE胎盘中发现了606个DMRs，出人意料的是，在EOPE诊断后，这些DMRs几乎不存在于cfDNA中。此外，胎盘、肝脏和肾脏特异性甲基化相对减少，而内皮特异性甲基化增加。在我们的队列中，只有2.7 - 8.4%的先前确定的区域显示出显著的甲基化差异。讨论不同组织对cfDNA的贡献可能解释了EOPE诊断后发现的DMRs。需要进一步的研究来更详细地阐明已鉴定的cfDNA dmr的（组织）起源。研究之间缺乏一致性仍然是一个重大的限制，可能是方法异质性的原因。

{"title":"Cell-free DNA methylation profiling in early-onset preeclampsia using methylated DNA sequencing","authors":"M.M. van Vliet , R.G. Boers , R.J.H. Galjaard , J.B. Boers , R.P.M. Steegers-Theunissen , J. Gribnau , S. Schoenmakers","doi":"10.1016/j.placenta.2025.12.006","DOIUrl":"10.1016/j.placenta.2025.12.006","url":null,"abstract":"<div><h3>Introduction</h3><div>Distinct DNA methylation profiles have been identified in maternal plasma cell-free DNA (cfDNA) in early-onset preeclampsia (EOPE). However, findings across studies often lack concordance and the biological mechanisms driving methylation differences are largely unknown. We aimed to identify EOPE-associated differentially methylated regions (DMRs), investigate changes in tissue-specific cfDNA contributions and validate previously reported EOPE-associated regions.</div></div><div><h3>Methods</h3><div>First-trimester cfDNA (n = 35) and cfDNA after diagnosis (n = 21) were collected from EOPE pregnancies and matched-controls. Placental tissues were collected from EOPE (n = 5) and control (n = 7) pregnancies. MeD-seq assays were performed to identify DMRs. Placental-contribution to cfDNA, cfDNA concentration, EOPE-specific placental markers, and methylation levels at previously identified EOPE-associated regions were compared between cases and controls. Additionally, liver-, kidney-, and endothelium-specific hypermethylated regions were identified using publicly available datasets and compared in cfDNA.</div></div><div><h3>Results</h3><div>We identified one DMR in the first trimester and 249 DMRs in our after diagnosis cohort. Total cfDNA concentration was 20-fold higher after EOPE diagnosis compared to controls (p < 0.001). We identified 606 DMRs in EOPE placentas, which unexpectedly were almost not present in cfDNA after EOPE diagnosis. Also, the placental-, liver-, and kidney-specific contributions were relatively decreased, while endothelium-specific methylation was increased. Only 2.7–8.4 % of previously identified regions showed significant differential methylation in our cohort.</div></div><div><h3>Discussion</h3><div>Differential tissue contributions to cfDNA likely account for DMRs identified after EOPE diagnosis. Further research is required to clarify the (tissue) origins of identified cfDNA DMRs in more detail. Lack of concordance across studies remains a significant limitation, potentially explained by methodological heterogeneity.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 186-195"},"PeriodicalIF":2.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145883732","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}

引用次数: 0

Determining a method for description and evaluation of heterogeneity of perfusion in the third-trimester placenta 确定描述和评估妊娠晚期胎盘灌注异质性的方法。

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-12-05 DOI: 10.1016/j.placenta.2025.11.014

Zoe Warland , Angela Xue , Samantha Thomas , Frank Wu , Tracie Barber , Josh Brandt , Claire Taylor , Trixie Kong , Alec William Welsh

Objectives

Many critical obstetric pathologies are associated with deficiencies in placental perfusion. However, there are limited diagnostic tools available to evaluate this and there is marked variability. We previously used the validated tool, Three-Dimensional Fractional Moving Blood Volume (3D-FMBV), combined with infra-red camera tracking technology to quantify perfusion in the entire third-trimester placenta. This pilot study aimed to describe and evaluate the heterogeneity of placental perfusion, visualise this as a ‘perfusion map,’ and assess changes over gestation.

Methods

This single-centre, prospective, cross-sectional study included 27 uncomplicated, third-trimester singleton pregnancies with anterior placentas. Multiple 3D Power Doppler Ultrasound (3D-PD-US) volumes were acquired with infra-red camera tracking coordinates, stitched and manually segmented to calculate the entire placental 3D-FMBV and volume. Heterogeneity was described using the coefficient of variation (CoV) of 3D-FMBV between defined cubic regions.

Results

In third-trimester placentas, mean CoV was 34.1 % (±5.0), declining as global perfusion increased (p = 0.02). With advancing gestation, perfusion non-significantly increased (p = 0.11) and became more homogenous (p = 0.27), while overall placental volume significantly increased (p = 0.02). Two-way mixed measure ICCs were 0.78, 0.63 and 0.95 for global 3D-FMBV, CoV and placental volume respectively.

Conclusion

This study successfully reconstructed entire third-trimester placentas using infra-red camera tracking technology, quantified perfusion using 3D-FMBV and demonstrated its heterogeneity. As gestation advances, perfusion appears to increase and become more uniform, potentially reflecting greater involvement of the placental bed to maximise fetoplacental exchange. Future work will explore automating our method, evaluating a larger cohort, and assessing differences in complicated pregnancies at-risk of stillbirth.

目的：许多关键的产科病理与胎盘灌注不足有关。然而，可用的诊断工具有限，而且存在明显的可变性。我们之前使用了经过验证的工具，三维分数运动血容量（3D-FMBV），结合红外相机跟踪技术来量化整个妊娠晚期胎盘的灌注。本初步研究旨在描述和评估胎盘灌注的异质性，将其可视化为“灌注图”，并评估妊娠期间的变化。方法：这项单中心、前瞻性、横断面研究包括27例无并发症的妊娠晚期单胎妊娠。利用红外摄像机跟踪坐标获取多个3D功率多普勒超声（3D- pd - us）体积，缝合后手工分割计算整个胎盘3D- fmbv和体积。使用3D-FMBV的变异系数（CoV）来描述定义的立方区域之间的异质性。结果：妊娠晚期胎盘平均CoV为34.1%（±5.0），随着全灌注量的增加而下降（p = 0.02）。随着妊娠的推进，灌注量无显著增加（p = 0.11），且更加均匀（p = 0.27），胎盘总体积显著增加（p = 0.02）。全球3D-FMBV、CoV和胎盘体积的双向混合测量ICCs分别为0.78、0.63和0.95。结论：本研究成功地利用红外相机跟踪技术重建了整个妊娠晚期胎盘，并利用3D-FMBV对灌注进行了量化，证实了其异质性。随着妊娠的进展，血流灌注似乎增加并且变得更加均匀，这可能反映了更多地参与胎盘床以最大化胎儿胎盘交换。未来的工作将探索使我们的方法自动化，评估更大的队列，并评估有死产风险的复杂妊娠的差异。

{"title":"Determining a method for description and evaluation of heterogeneity of perfusion in the third-trimester placenta","authors":"Zoe Warland , Angela Xue , Samantha Thomas , Frank Wu , Tracie Barber , Josh Brandt , Claire Taylor , Trixie Kong , Alec William Welsh","doi":"10.1016/j.placenta.2025.11.014","DOIUrl":"10.1016/j.placenta.2025.11.014","url":null,"abstract":"<div><h3>Objectives</h3><div>Many critical obstetric pathologies are associated with deficiencies in placental perfusion. However, there are limited diagnostic tools available to evaluate this and there is marked variability. We previously used the validated tool, Three-Dimensional Fractional Moving Blood Volume (3D-FMBV), combined with infra-red camera tracking technology to quantify perfusion in the entire third-trimester placenta. This pilot study aimed to describe and evaluate the heterogeneity of placental perfusion, visualise this as a ‘perfusion map,’ and assess changes over gestation.</div></div><div><h3>Methods</h3><div>This single-centre, prospective, cross-sectional study included 27 uncomplicated, third-trimester singleton pregnancies with anterior placentas. Multiple 3D Power Doppler Ultrasound (3D-PD-US) volumes were acquired with infra-red camera tracking coordinates, stitched and manually segmented to calculate the entire placental 3D-FMBV and volume. Heterogeneity was described using the coefficient of variation (CoV) of 3D-FMBV between defined cubic regions.</div></div><div><h3>Results</h3><div>In third-trimester placentas, mean CoV was 34.1 % (±5.0), declining as global perfusion increased (p = 0.02). With advancing gestation, perfusion non-significantly increased (p = 0.11) and became more homogenous (p = 0.27), while overall placental volume significantly increased (p = 0.02). Two-way mixed measure ICCs were 0.78, 0.63 and 0.95 for global 3D-FMBV, CoV and placental volume respectively.</div></div><div><h3>Conclusion</h3><div>This study successfully reconstructed entire third-trimester placentas using infra-red camera tracking technology, quantified perfusion using 3D-FMBV and demonstrated its heterogeneity. As gestation advances, perfusion appears to increase and become more uniform, potentially reflecting greater involvement of the placental bed to maximise fetoplacental exchange. Future work will explore automating our method, evaluating a larger cohort, and assessing differences in complicated pregnancies at-risk of stillbirth.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 109-116"},"PeriodicalIF":2.5,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145756755","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}

引用次数: 0

Impact of SARS-CoV-2 omicron variant on placental pathology and perinatal outcomes: a retrospective comparison of vaccinated, partially vaccinated and unvaccinated pregnant women SARS-CoV-2组粒变异对胎盘病理和围产期结局的影响：接种疫苗、部分接种疫苗和未接种疫苗的孕妇的回顾性比较

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-12-05 DOI: 10.1016/j.placenta.2025.12.003

Brenda F. Narice , Erick Yturralde , Sophie Stenton , Michael Peny , Nadia Burgess , Dilly Anumba , Marta C. Cohen

Introduction

Previous SARS-CoV-2 variants were linked to severe maternal COVID-19 and distinctive placentitis, contributing to adverse pregnancy outcomes. With the emergence of the omicron variant, which demonstrated lower severity, the impact on placental histology and pregnancy outcomes remains unclear. We aimed to characterise placental pathology during the omicron wave in the UK and assess associations with maternal vaccination status and perinatal outcomes.

Methods

A retrospective analysis involved 195 placentas from pregnancies with maternal SARS-CoV-2 infection during the omicron wave at our institution. Maternal demographics, vaccination status, pregnancy and neonatal outcomes were collected. Placental specimens were examined for pathological features. Statistical analysis was performed to evaluate differences between vaccinated (fully/partially) and unvaccinated groups.

Results

No cases of severe SARS-CoV-2 placentitis were observed. Common histological findings included acute chorioamnionitis, distal villous maldevelopment, villitis of unknown etiology, intervillous thrombosis, and chronic deciduitis. Maternal vascular malperfusion occurred across all groups, with a fragile signal in partially vaccinated women. Maternal and perinatal outcomes were favourable, with no maternal deaths, stillbirths or neonatal mortality.

Discussion

Placental pathology during the omicron wave lacked the severe placentitis previously reported with alpha and delta variants and correlated with fewer adverse maternal and neonatal outcomes. Vascular malperfusion lesions were observed across all vaccination groups, with a fragile statistical signal in the small partially vaccinated group that did not remain robust on sensitivity analyses. Placental pathology with omicron is generally milder and provide novel insights into variant-specific placental effects, with no clear evidence of increased vascular pathology according to vaccination status.

先前的SARS-CoV-2变异与严重的母体COVID-19和独特的胎盘炎有关，导致不良妊娠结局。随着组粒变异的出现，其严重程度较低，对胎盘组织学和妊娠结局的影响尚不清楚。我们的目的是在英国微米波期间描述胎盘病理特征，并评估与母亲接种疫苗状况和围产期结局的关系。方法：回顾性分析我院195例母体感染SARS-CoV-2的孕妇胎盘。收集了孕产妇人口统计、疫苗接种状况、妊娠和新生儿结局。检查胎盘标本的病理特征。对接种（全部/部分）疫苗组和未接种疫苗组的差异进行统计分析。结果：未发现重症SARS-CoV-2胎盘炎病例。常见的组织学表现包括急性绒毛膜羊膜炎、远端绒毛发育不良、不明原因的绒毛炎、绒毛间血栓形成和慢性蜕膜炎。所有组均发生母体血管灌注不良，在部分接种疫苗的妇女中有一个脆弱的信号。产妇和围产期结局良好，没有产妇死亡、死产或新生儿死亡。讨论：染色体波期间的胎盘病理缺乏先前报道的严重的α和δ变异胎盘炎，并且与较少的不良产妇和新生儿结局相关。在所有接种组中都观察到血管灌注不良病变，在少数部分接种组中有一个脆弱的统计信号，在敏感性分析中没有保持稳健。组粒的胎盘病理通常较温和，并为变异特异性胎盘效应提供了新的见解，没有明确的证据表明根据疫苗接种状态血管病理增加。

{"title":"Impact of SARS-CoV-2 omicron variant on placental pathology and perinatal outcomes: a retrospective comparison of vaccinated, partially vaccinated and unvaccinated pregnant women","authors":"Brenda F. Narice , Erick Yturralde , Sophie Stenton , Michael Peny , Nadia Burgess , Dilly Anumba , Marta C. Cohen","doi":"10.1016/j.placenta.2025.12.003","DOIUrl":"10.1016/j.placenta.2025.12.003","url":null,"abstract":"<div><h3>Introduction</h3><div>Previous SARS-CoV-2 variants were linked to severe maternal COVID-19 and distinctive placentitis, contributing to adverse pregnancy outcomes. With the emergence of the omicron variant, which demonstrated lower severity, the impact on placental histology and pregnancy outcomes remains unclear. We aimed to characterise placental pathology during the omicron wave in the UK and assess associations with maternal vaccination status and perinatal outcomes.</div></div><div><h3>Methods</h3><div>A retrospective analysis involved 195 placentas from pregnancies with maternal SARS-CoV-2 infection during the omicron wave at our institution. Maternal demographics, vaccination status, pregnancy and neonatal outcomes were collected. Placental specimens were examined for pathological features. Statistical analysis was performed to evaluate differences between vaccinated (fully/partially) and unvaccinated groups.</div></div><div><h3>Results</h3><div>No cases of severe SARS-CoV-2 placentitis were observed. Common histological findings included acute chorioamnionitis, distal villous maldevelopment, villitis of unknown etiology, intervillous thrombosis, and chronic deciduitis. Maternal vascular malperfusion occurred across all groups, with a fragile signal in partially vaccinated women. Maternal and perinatal outcomes were favourable, with no maternal deaths, stillbirths or neonatal mortality.</div></div><div><h3>Discussion</h3><div>Placental pathology during the omicron wave lacked the severe placentitis previously reported with alpha and delta variants and correlated with fewer adverse maternal and neonatal outcomes. Vascular malperfusion lesions were observed across all vaccination groups, with a fragile statistical signal in the small partially vaccinated group that did not remain robust on sensitivity analyses. Placental pathology with omicron is generally milder and provide novel insights into variant-specific placental effects, with no clear evidence of increased vascular pathology according to vaccination status.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 71-75"},"PeriodicalIF":2.5,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145715451","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}

引用次数: 0

Influence of perillyl alcohol on human umbilical vein relaxation: mechanisms involving calcium channels and protein kinase C 紫苏醇对人脐静脉舒张的影响：涉及钙通道和蛋白激酶C的机制

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-12-05 DOI: 10.1016/j.placenta.2025.12.001

Carla Mikevely de Sena Bastos , Andressa de Alencar Silva , Paulo Ricardo Batista , Maria Raquel da Silva Duarte , Laíza Maria Ulisses Magalhães , Yedda Maria Lobo Soares de Matos , Renata Evaristo Rodrigues Duarte , Irwin Rose Alencar de Menezes , Luís Pereira-de-Morais , Roseli Barbosa

Introduction

Perillyl alcohol (POH) is a monoterpene found in the essential oil of several plants. Few studies have evaluated its effects on isolated vessels. Therefore, this study aimed to evaluate the effect of POH on human umbilical veins (HUV).

Method

The isometric tension of endothelium-denuded HUV rings was recorded in different functional assays in an organ bath. The effect of POH (1–2000 μM) was evaluated on the basal and active tone of the rings, and possible mechanisms of action at transmembrane and intracellular levels were proposed.

Results

POH induced a biphasic effect on the basal tone of the rings and inhibited vasoconstriction mediated by depolarization (KCl 60 mM) and agonists (5-HT, His; 10 μM or BK; 0.1 μM). In Ca²⁺-free solution, POH inhibited vasoconstriction induced by BaCl₂ (3–10 mM) and PMA (10 μM), but not 5-HT (10 μM). The potency and efficacy of the vasorelaxant effect of POH were not significantly modified in the presence of K⁺ channel blockers (TEA 1 or 10 mM, 4-AP 1 mM, or Gli 10 μM) and endothelial pathways blockers (L-NAME 1 mM or ODQ 100 μM).

Discussion

Our findings suggest that the mode of action of POH in HUV involves transmembrane (blocking extracellular Ca²⁺ influx) and intracellular (inhibiting PKC) pathways, with less involvement of K⁺ channels and NOS and GC enzymes. Thus, the present study contributes to the discovery of new pharmacological candidates for disorders that increase umbilical vascular resistance.

紫苏醇（Perillyl alcohol， POH）是一种存在于多种植物精油中的单萜化合物。很少有研究评估其对孤立血管的影响。因此，本研究旨在评价POH对人脐静脉（HUV）的影响。方法：在器官浴中记录内皮剥离HUV环的等长张力。研究了POH （1 ~ 2000 μM）对环的基础张力和活性张力的影响，并从跨膜和细胞内水平提出了可能的作用机制。结果：POH诱导双相作用于环的基底张力，抑制去极化（KCl 60 mM）和激动剂（5-HT、His、10 μM或BK、0.1 μM）介导的血管收缩。在无Ca2+溶液中，POH对BaCl2 （3-10 mM）和PMA （10 μM）诱导的血管收缩有抑制作用，但对5-HT （10 μM）没有抑制作用。在K+通道阻滞剂（TEA 1或10 mM， 4-AP 1 mM，或Gli 10 μM）和内皮通路阻滞剂（L-NAME 1 mM或ODQ 100 μM）的存在下，POH的血管松弛作用的效力和效果没有明显改变。讨论：我们的研究结果表明，POH在HUV中的作用模式涉及跨膜（阻断细胞外Ca2+内流）和细胞内（抑制PKC）途径，较少参与K+通道和NOS和GC酶。因此，本研究有助于发现新的药理学候选疾病，增加脐带血管阻力。

{"title":"Influence of perillyl alcohol on human umbilical vein relaxation: mechanisms involving calcium channels and protein kinase C","authors":"Carla Mikevely de Sena Bastos , Andressa de Alencar Silva , Paulo Ricardo Batista , Maria Raquel da Silva Duarte , Laíza Maria Ulisses Magalhães , Yedda Maria Lobo Soares de Matos , Renata Evaristo Rodrigues Duarte , Irwin Rose Alencar de Menezes , Luís Pereira-de-Morais , Roseli Barbosa","doi":"10.1016/j.placenta.2025.12.001","DOIUrl":"10.1016/j.placenta.2025.12.001","url":null,"abstract":"<div><h3>Introduction</h3><div>Perillyl alcohol (POH) is a monoterpene found in the essential oil of several plants. Few studies have evaluated its effects on isolated vessels. Therefore, this study aimed to evaluate the effect of POH on human umbilical veins (HUV).</div></div><div><h3>Method</h3><div>The isometric tension of endothelium-denuded HUV rings was recorded in different functional assays in an organ bath. The effect of POH (1–2000 μM) was evaluated on the basal and active tone of the rings, and possible mechanisms of action at transmembrane and intracellular levels were proposed.</div></div><div><h3>Results</h3><div>POH induced a biphasic effect on the basal tone of the rings and inhibited vasoconstriction mediated by depolarization (KCl 60 mM) and agonists (5-HT, His; 10 μM or BK; 0.1 μM). In Ca<sup>2+</sup>-free solution, POH inhibited vasoconstriction induced by BaCl<sub>2</sub> (3–10 mM) and PMA (10 μM), but not 5-HT (10 μM). The potency and efficacy of the vasorelaxant effect of POH were not significantly modified in the presence of K<sup>+</sup> channel blockers (TEA 1 or 10 mM, 4-AP 1 mM, or Gli 10 μM) and endothelial pathways blockers (L-NAME 1 mM or ODQ 100 μM).</div></div><div><h3>Discussion</h3><div>Our findings suggest that the mode of action of POH in HUV involves transmembrane (blocking extracellular Ca<sup>2+</sup> influx) and intracellular (inhibiting PKC) pathways, with less involvement of K<sup>+</sup> channels and NOS and GC enzymes. Thus, the present study contributes to the discovery of new pharmacological candidates for disorders that increase umbilical vascular resistance.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 84-94"},"PeriodicalIF":2.5,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743908","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}

引用次数: 0

Lymphatic mimicry of spiral arteries is impaired by human sFLT1 overexpression in a preeclampsia mouse model 在子痫前期小鼠模型中，人类sFLT1过表达会损害螺旋动脉的淋巴模拟。

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-12-03 DOI: 10.1016/j.placenta.2025.12.002

Alina Edinger , Charlotte Cathrin Mohr , Elisa Marie Elfroth , Bernd Walkenfort , Sylvia Voortmann , Rainer Kimmig , Elke Winterhager , Alexandra Gellhaus

Introduction

The pregnancy disorder preeclampsia (PE) is characterized by maternal hypertension and reduced spiral artery (SpA) remodeling which is aggravated by increased levels of anti-angiogenic soluble fms-related tyrosine kinase 1 (sFLT1). One process contributing to physiological SpA remodeling in early pregnancy is the expression of lymphatic receptors on endothelial cells of SpAs, which is called lymphatic mimicry. Adverse lymphatic mimicry of SpAs is theorized to play a role in the pathophysiology of PE, but was not analyzed under preeclamptic conditions.

Methods

Using the transgenic PE/FGR mouse model with ubiquitous overexpression of human sFLT1 (hsFLT1), we focused on lymphatic marker expression in early pregnancy at 12.5 dpc and 14.5 dpc and evaluated the reduction of SpA remodeling as well as mRNA expression of lymphatic markers like Lyve1, Pdpn, or Prox1 in the mesometrial triangle (MT) of murine placentas. Additionally, uterine NK cell distribution was analyzed via electron microscopy and immunohistochemistry in placentas of PE animals.

Results

We could prove significantly reduced levels of Pdpn and Nrp1 mRNA in MT of PE placentas. Additionally, the mRNA expression of chemokines like Ccl21 were reduced at from 12.5 dpc until 14.5 dpc which could inhibit infiltration of uterine NK cell populations in these compartments in later pregnancy.

Discussion

With this study we could show that increased levels of human sFLT1 interfere with early spiral artery (SpA) remodeling processes and could inhibit lymphatic mimicry of SpA. Immune cell infiltration until 14.5 dpc could be decreased by downregulation of the chemotactic chemokine Ccl21.

妊娠障碍先兆子痫（PE）的特点是产妇高血压和螺旋动脉（SpA）重塑减少，而抗血管生成可溶性纤维相关酪氨酸激酶1 （sFLT1）水平升高会加重螺旋动脉重塑。孕早期SpA生理重塑的一个过程是SpA内皮细胞淋巴受体的表达，这被称为淋巴模仿。理论上，spa的不良淋巴模仿在PE的病理生理中起作用，但未在子痫前期条件下进行分析。方法：采用普遍过表达人sFLT1 （hsFLT1）的转基因PE/FGR小鼠模型，重点观察妊娠早期12.5、14.5胎龄时淋巴标记物的表达情况，并对小鼠胎盘中系膜三角区（mesometrial triangle， MT）淋巴标记物Lyve1、Pdpn、Prox1 mRNA表达及SpA重塑的减少情况进行评价。通过电镜和免疫组化分析PE动物胎盘中子宫NK细胞的分布。结果：PE胎盘MT中Pdpn和Nrp1 mRNA水平明显降低。此外，趋化因子如Ccl21的mRNA表达从12.5 dpc降低到14.5 dpc，这可能抑制妊娠后期子宫NK细胞群在这些腔室的浸润。讨论：通过这项研究，我们可以表明，人类sFLT1水平的升高会干扰早期螺旋动脉（SpA）重塑过程，并可能抑制SpA的淋巴模仿。通过下调趋化趋化因子Ccl21，可减少免疫细胞浸润至14.5 dpc。

{"title":"Lymphatic mimicry of spiral arteries is impaired by human sFLT1 overexpression in a preeclampsia mouse model","authors":"Alina Edinger , Charlotte Cathrin Mohr , Elisa Marie Elfroth , Bernd Walkenfort , Sylvia Voortmann , Rainer Kimmig , Elke Winterhager , Alexandra Gellhaus","doi":"10.1016/j.placenta.2025.12.002","DOIUrl":"10.1016/j.placenta.2025.12.002","url":null,"abstract":"<div><h3>Introduction</h3><div>The pregnancy disorder preeclampsia (PE) is characterized by maternal hypertension and reduced spiral artery (SpA) remodeling which is aggravated by increased levels of anti-angiogenic soluble fms-related tyrosine kinase 1 (sFLT1). One process contributing to physiological SpA remodeling in early pregnancy is the expression of lymphatic receptors on endothelial cells of SpAs, which is called lymphatic mimicry. Adverse lymphatic mimicry of SpAs is theorized to play a role in the pathophysiology of PE, but was not analyzed under preeclamptic conditions.</div></div><div><h3>Methods</h3><div>Using the transgenic PE/FGR mouse model with ubiquitous overexpression of human sFLT1 (hsFLT1), we focused on lymphatic marker expression in early pregnancy at 12.5 dpc and 14.5 dpc and evaluated the reduction of SpA remodeling as well as mRNA expression of lymphatic markers like <em>Lyve1</em>, <em>Pdpn</em>, or <em>Prox1</em> in the mesometrial triangle (MT) of murine placentas. Additionally, uterine NK cell distribution was analyzed via electron microscopy and immunohistochemistry in placentas of PE animals.</div></div><div><h3>Results</h3><div>We could prove significantly reduced levels of <em>Pdpn</em> and <em>Nrp1</em> mRNA in MT of PE placentas. Additionally, the mRNA expression of chemokines like <em>Ccl21</em> were reduced at from 12.5 dpc until 14.5 dpc which could inhibit infiltration of uterine NK cell populations in these compartments in later pregnancy.</div></div><div><h3>Discussion</h3><div>With this study we could show that increased levels of human sFLT1 interfere with early spiral artery (SpA) remodeling processes and could inhibit lymphatic mimicry of SpA. Immune cell infiltration until 14.5 dpc could be decreased by downregulation of the chemotactic chemokine <em>Ccl21</em>.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 53-62"},"PeriodicalIF":2.5,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687873","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}

引用次数: 0

Robert Pijnenborg – An appreciation Robert Pijnenborg——感谢

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-12-01 DOI: 10.1016/j.placenta.2025.11.009

John Aplin

引用次数: 0