Placenta最新文献

The role of leukemia inhibitory factor in regulating angiogenesis-related gene expression in a mouse model of recurrent miscarriage

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-04-13 DOI: 10.1016/j.placenta.2025.04.009

Zahra Allahyari , Narges Nikoonahad Lotfabadi , Fateme Zare

Background

Recurrent miscarriage is an early pregnancy complication that affects approximately 1–3 % of pregnant couples. Leukemia Inhibitory Factor (LIF) plays an important role in various biological processes, including angiogenesis and pregnancy. This study aimed to evaluate the role of LIF in regulating angiogenesis-related genes in a mouse model of recurrent miscarriage.

Method

Female CBA/J mice mated with DBA/2J males were utilized as a miscarriage model. The study population was randomly assigned to three groups, normal group, mating female CBA/J mouse with male Balb/c without injection; miscarriage model control group with PBS injection; and the miscarriage group, in which LIF was injected. Following detection of a vaginal plug, mice were dissected on days 4, 7, and 14 of pregnancy. Uterine and placental tissues were collected to assess the expression of angiogenesis-related genes, including VEGF, PDGF, ANG1, FGF, and TGF-β, using real-time PCR.

Result

Data analysis revealed no significant differences in the expression of angiogenesis-related genes on days 4 and 7 of pregnancy compared with the control group. However, on day 14 of pregnancy, the expression of VEGF and TGF-β was significantly elevated in the miscarriage group receiving LIF compared to other groups (P = 0.03 and P = 0.04, respectively). The placental expression of the studied genes also exhibited a non-significant increase in the miscarriage group, with VEGF and TGF-β showing the most prominent increases, although these changes were not statistically significant. Correlation analysis between uterine and placental gene expression on day 14 revealed no significant association.

Conclusion

LIF regulates the uterine and placental expression of angiogenesis-related genes, particularly VEGF and TGF-β. These findings highlight the role of LIF in regulating angiogenesis-related gene expression and suggest that LIF could be a potential therapeutic candidate for improving pregnancy outcomes in cases of recurrent miscarriage.

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引用次数: 0

Placental magnesium transport-related mRNA expression is not associated with serum magnesium in singletons and twins

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-04-09 DOI: 10.1016/j.placenta.2025.04.007

Cheawon Lee , Yoon Ha Kim , Myeong Gyun Choi , Jong Woon Kim , Clara Yongjoo Park

The mechanisms of placental magnesium (Mg) transport are unknown, especially in twins. We cross-sectionally investigated the association of Mg transport-related protein mRNA expression with serum Mg, placental Mg concentration (p[Mg]), and placenta weight in singleton and twin placentas from 67 mothers. Maternal and cord blood serum Mg were not associated with placental mRNA expression. TRPM6 and TRPM7 mRNAs were positively associated with placental weight in twins while TRPM7 mRNA was positively associated with p[Mg] in singletons. In placentas of relatively healthy women, TRPM6 and TRPM7 may regulate p[Mg] and growth, rather than serum Mg, especially in twin placentas.

引用次数: 0

Characterising the role of placental angiotensin-converting enzyme 2 (ACE2) during the onset of oxidative insult by hypoxia/reoxygenation: Implications for fetal growth restriction

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-04-08 DOI: 10.1016/j.placenta.2025.04.008

India A. Brooker , Joshua J. Fisher , Sarah J. Delforce , Saije K. Endacott , Eugenie R. Lumbers , Jessie M. Sutherland , Kirsty G. Pringle

Introduction

Fetal growth restriction (FGR) is a leading cause of infant morbidity and mortality. Approximately 60% of FGR cases result from placental dysfunction, often due to defective remodelling of the uterine vasculature and subsequent exposure to hypoxia/reoxygenation that induces oxidative stress. Angiotensin-converting enzyme 2 (ACE2) counteracts the ACE-driven axis of the renin-angiotensin system and is reduced in FGR placentae. We aimed to investigate the role of ACE2 in protecting against placental oxidative stress induced via a hypoxia/reoxygenation event.

Methods

Term placental explants were exposed to normoxia (8% O₂) for 6 hrs or were treated with media alone or recombinant human (rh)ACE2 and exposed to a hypoxia/reoxygenation insult (1 hr hypoxia (1% O₂), 5 hrs normoxia). Oxidative stress markers, and ACE and ACE2 mRNA, protein, or activity were assessed.

Results

ACE2 mRNA expression was increased with hypoxia/reoxygenation compared with normoxia (p=0.045). Hypoxia/reoxygenation significantly increased placental mRNA expression of the oxidative enzymes NOX4 and NOX5 compared with normoxia (p=0.021 and 0.023). NOX5 protein was not significantly different between normoxic controls and hypoxia/reoxygenation; however, rhACE2 significantly reduced NOX5 protein levels (p=0.015). Antioxidant activity of SOD decreased (p=0.028), while CAT increased with hypoxia/reoxygenation (p=0.010). Placental Nrf2 and NQO1 mRNA expression increased with rhACE2 compared with hypoxia/reoxygenation alone (p=0.038 and 0.013).

Conclusion

We have characterised the redox-sensitive changes that occur in the placenta due to defective placentation and hypoxia/reoxygenation and have shown for the first time the role of placental ACE2 in mitigating oxidative insult associated with hypoxia/reoxygenation.

{"title":"Characterising the role of placental angiotensin-converting enzyme 2 (ACE2) during the onset of oxidative insult by hypoxia/reoxygenation: Implications for fetal growth restriction","authors":"India A. Brooker , Joshua J. Fisher , Sarah J. Delforce , Saije K. Endacott , Eugenie R. Lumbers , Jessie M. Sutherland , Kirsty G. Pringle","doi":"10.1016/j.placenta.2025.04.008","DOIUrl":"10.1016/j.placenta.2025.04.008","url":null,"abstract":"<div><h3>Introduction</h3><div>Fetal growth restriction (FGR) is a leading cause of infant morbidity and mortality. Approximately 60% of FGR cases result from placental dysfunction, often due to defective remodelling of the uterine vasculature and subsequent exposure to hypoxia/reoxygenation that induces oxidative stress. Angiotensin-converting enzyme 2 (ACE2) counteracts the ACE-driven axis of the renin-angiotensin system and is reduced in FGR placentae. We aimed to investigate the role of ACE2 in protecting against placental oxidative stress induced via a hypoxia/reoxygenation event.</div></div><div><h3>Methods</h3><div>Term placental explants were exposed to normoxia (8% O<sub>2</sub>) for 6 hrs or were treated with media alone or recombinant human (rh)ACE2 and exposed to a hypoxia/reoxygenation insult (1 hr hypoxia (1% O<sub>2</sub>), 5 hrs normoxia). Oxidative stress markers, and ACE and ACE2 mRNA, protein, or activity were assessed.</div></div><div><h3>Results</h3><div><em>ACE2</em> mRNA expression was increased with hypoxia/reoxygenation compared with normoxia (<em>p</em>=0.045). Hypoxia/reoxygenation significantly increased placental mRNA expression of the oxidative enzymes <em>NOX4</em> and <em>NOX5</em> compared with normoxia (<em>p</em>=0.021 and 0.023). NOX5 protein was not significantly different between normoxic controls and hypoxia/reoxygenation; however, rhACE2 significantly reduced NOX5 protein levels (<em>p</em>=0.015). Antioxidant activity of SOD decreased (<em>p</em>=0.028), while CAT increased with hypoxia/reoxygenation (<em>p</em>=0.010). Placental <em>Nrf2</em> and <em>NQO1</em> mRNA expression increased with rhACE2 compared with hypoxia/reoxygenation alone (<em>p</em>=0.038 and 0.013).</div></div><div><h3>Conclusion</h3><div>We have characterised the redox-sensitive changes that occur in the placenta due to defective placentation and hypoxia/reoxygenation and have shown for the first time the role of placental ACE2 in mitigating oxidative insult associated with hypoxia/reoxygenation.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"165 ","pages":"Pages 82-90"},"PeriodicalIF":3.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824708","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

Grading magnetic resonance imaging signs for diagnosing invasive placenta accreta spectrum disorders

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-04-08 DOI: 10.1016/j.placenta.2025.04.004

Fengying Chen , Dazhi Fan , Rufang Chen , Ying Zhang , Gan Tian , Donghua Zhou , Haojie Ning , Dawei Zhang , Shuixing Zhang

Introduction

Placenta accreta spectrum (PAS) disorders result from abnormal placental attachment, leading to varying degrees of myometrial invasion. Magnetic resonance imaging (MRI) plays a crucial role in assessing the depth and extent of placental invasion. This study aims to evaluate the correlation between quantified MRI findings and the diagnosis of PAS, as classified according to the FIGO system.

Materials and methods

A retrospective analysis was conducted on 556 high-risk PAS patients, defined as those with placenta previa or a history of previous cesarean sections. Ten predefined MRI signs were assessed board certified radiologists. Multivariate logistic regression was used to identify independent predictors of invasive PAS. The positive predictive value (PPV) and negative predictive value (NPV) were calculated to assess the diagnostic performance of signs.

Results

Among the 556 cases, 150 (26.98 %) were classified as non-PAS, 180 (32.37 %) as placenta accreta, 158 (28.42 %) as placenta increta, and 68 (12.23 %) as placenta percreta. Four MRI signs were identified as significant predictors of invasive PAS: bladder wall interruption (odd ratio [OR] = 160.17), placental ischemic infarction (OR = 19.91), placental protrusion (OR = 14.66), and myometrial thinning (OR = 14.07). The PPV of these signs ranged from 70 % to 85 %, while the NPV ranged from 65 % to 72 %. Multivariate analysis confirmed these MRI findings as independent predictors of invasive PAS.

Conclusions

This study identified four key MRI signs as reliable predictors of invasive PAS, which can effectively inform clinical decision-making regarding surgical interventions, such as cesarean hysterectomy.

{"title":"Grading magnetic resonance imaging signs for diagnosing invasive placenta accreta spectrum disorders","authors":"Fengying Chen , Dazhi Fan , Rufang Chen , Ying Zhang , Gan Tian , Donghua Zhou , Haojie Ning , Dawei Zhang , Shuixing Zhang","doi":"10.1016/j.placenta.2025.04.004","DOIUrl":"10.1016/j.placenta.2025.04.004","url":null,"abstract":"<div><h3>Introduction</h3><div>Placenta accreta spectrum (PAS) disorders result from abnormal placental attachment, leading to varying degrees of myometrial invasion. Magnetic resonance imaging (MRI) plays a crucial role in assessing the depth and extent of placental invasion. This study aims to evaluate the correlation between quantified MRI findings and the diagnosis of PAS, as classified according to the FIGO system.</div></div><div><h3>Materials and methods</h3><div>A retrospective analysis was conducted on 556 high-risk PAS patients, defined as those with placenta previa or a history of previous cesarean sections. Ten predefined MRI signs were assessed board certified radiologists. Multivariate logistic regression was used to identify independent predictors of invasive PAS. The positive predictive value (PPV) and negative predictive value (NPV) were calculated to assess the diagnostic performance of signs.</div></div><div><h3>Results</h3><div>Among the 556 cases, 150 (26.98 %) were classified as non-PAS, 180 (32.37 %) as placenta accreta, 158 (28.42 %) as placenta increta, and 68 (12.23 %) as placenta percreta. Four MRI signs were identified as significant predictors of invasive PAS: bladder wall interruption (odd ratio [OR] = 160.17), placental ischemic infarction (OR = 19.91), placental protrusion (OR = 14.66), and myometrial thinning (OR = 14.07). The PPV of these signs ranged from 70 % to 85 %, while the NPV ranged from 65 % to 72 %. Multivariate analysis confirmed these MRI findings as independent predictors of invasive PAS.</div></div><div><h3>Conclusions</h3><div>This study identified four key MRI signs as reliable predictors of invasive PAS, which can effectively inform clinical decision-making regarding surgical interventions, such as cesarean hysterectomy.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"165 ","pages":"Pages 62-72"},"PeriodicalIF":3.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143816434","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

Characteristics and clinical consequences of bipartite monochorionic twin placentas

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-04-07 DOI: 10.1016/j.placenta.2025.04.003

M.J.A. van de Sande , E. Lopriore , L. Lewi , J.A. Spekman , M.C. Haak , E.J.T. Verweij , C.C.M.M. Lap , L.E. van der Meeren , F. Slaghekke , L.S.A. Tollenaar

Objective

To investigate the angioarchitecture and clinical consequences of bipartite monochorionic (MC) twin placentas.

Methods

Case-control study of MC twin placentas examined at the Leiden University Medical Center (The Netherlands) and University Hospitals Leuven (Belgium). We injected all MC placentas with colored dye and studied the characteristics of bipartite placentas. In addition, we evaluated the concomitant occurrence of clinical complications including twin-to-twin transfusion syndrome (TTTS), twin anemia polycythemia sequence (TAPS) and selective fetal growth restriction (sFGR).

Results

Bipartite placentas were detected in 2.1 % (38/1804) of MC twin placentas. In the subgroup of MC twin placentas not treated with laser surgery, vascular anastomoses were detected in 75 % (21/28) of bipartite placentas versus 96 % (1002/1030) of non-bipartite placentas (p < 0.001). The total number of vascular anastomoses were lower in bipartite placentas (4 (IQR 0–8)) versus non-bipartite placentas (8 (IQR 5–13)) (p < 0.001). Arterio-venous (AV) anastomoses were found less often in bipartite placentas compared to non-bipartite placentas: 68 % (19/28) versus 96 % (984/1022), respectively (p < 0.001). Similarly, arterio-arterial (AA) anastomoses were detected less frequently in bipartite versus non-bipartite placentas: 50 % (14/28) versus 82 % (841/1027), respectively (p < 0.001). TTTS, TAPS and sFGR were diagnosed in 26 % (10/38), 13 % (5/38) and 5 % (2/38) of bipartite placentas, respectively.

Conclusion

Although bipartite placentas in MC twin pregnancies are rare, the majority have vascular anastomoses and may therefore develop complications such as TTTS, TAPS or sFGR.

{"title":"Characteristics and clinical consequences of bipartite monochorionic twin placentas","authors":"M.J.A. van de Sande , E. Lopriore , L. Lewi , J.A. Spekman , M.C. Haak , E.J.T. Verweij , C.C.M.M. Lap , L.E. van der Meeren , F. Slaghekke , L.S.A. Tollenaar","doi":"10.1016/j.placenta.2025.04.003","DOIUrl":"10.1016/j.placenta.2025.04.003","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate the angioarchitecture and clinical consequences of bipartite monochorionic (MC) twin placentas.</div></div><div><h3>Methods</h3><div>Case-control study of MC twin placentas examined at the Leiden University Medical Center (The Netherlands) and University Hospitals Leuven (Belgium). We injected all MC placentas with colored dye and studied the characteristics of bipartite placentas. In addition, we evaluated the concomitant occurrence of clinical complications including twin-to-twin transfusion syndrome (TTTS), twin anemia polycythemia sequence (TAPS) and selective fetal growth restriction (sFGR).</div></div><div><h3>Results</h3><div>Bipartite placentas were detected in 2.1 % (38/1804) of MC twin placentas. In the subgroup of MC twin placentas not treated with laser surgery, vascular anastomoses were detected in 75 % (21/28) of bipartite placentas versus 96 % (1002/1030) of non-bipartite placentas (p < 0.001). The total number of vascular anastomoses were lower in bipartite placentas (4 (IQR 0–8)) versus non-bipartite placentas (8 (IQR 5–13)) (p < 0.001). Arterio-venous (AV) anastomoses were found less often in bipartite placentas compared to non-bipartite placentas: 68 % (19/28) versus 96 % (984/1022), respectively (p < 0.001). Similarly, arterio-arterial (AA) anastomoses were detected less frequently in bipartite versus non-bipartite placentas: 50 % (14/28) versus 82 % (841/1027), respectively (p < 0.001). TTTS, TAPS and sFGR were diagnosed in 26 % (10/38), 13 % (5/38) and 5 % (2/38) of bipartite placentas, respectively.</div></div><div><h3>Conclusion</h3><div>Although bipartite placentas in MC twin pregnancies are rare, the majority have vascular anastomoses and may therefore develop complications such as TTTS, TAPS or sFGR.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"165 ","pages":"Pages 76-81"},"PeriodicalIF":3.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824707","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

Increasing incidence of hypertensive disorders of pregnancy and association with decreased GFR and albuminuria: The need for post-partum follow-up

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-04-04 DOI: 10.1016/j.placenta.2025.03.017

Carolina Gracia-Iguacel , Manuel Pérez Torán , Miguel Alvaro Navidad , Begoña Gómez Pérez , José Miguel Arce-Obieta , Cristina Morocho-Pindo , Emilio González-Parra , Ignacio Mahillo , Alberto Ortiz

Background

Hypertensive disorders of pregnancy (HDP) are associated with increased postpartum risk of cardiovascular disease or kidney failure. However, there is scarce information on the association with actionable kidney outcomes that should be treated to prevent progression to kidney failure.

Objectives

To evaluate the incidence of HDP over time and its association with kidney function, hypertension, and albuminuria during follow-up after discharge.

Methods

Single center retrospective cohort study of women without previous history of CKD among 20484 deliveries over 10 years.

Results

From 2008 to 2017, HDP was diagnosed in 846 (4.13 %) pregnant women. The incidence increased over time and was higher in women from Africa and America than in European women. The Nephrology department evaluated 210 (27 %) women with HDP during hospitalization and 170 (21 %) during follow-up. At follow-up, 5.3 % of the 150 women with available follow-up eGFR data had decreased eGFR (<90 ml/min/1.73 m²), 16.1 % albuminuria ≥30 mg/g and 8.6 % persistent hypertension. In multivariate analysis, gestational diabetes mellitus [OR 8.03 (95 % CI: 1.49–43.13; p 0.01)] and higher number of pregnancies [OR: 1.27 (95 % CI: 1.00–1.62; p 0.04)] were associated with persistent hypertension; diabetes mellitus [OR 14.07 (1.59–123.89); p = 0.02] with decreased glomerular filtration rate; and obesity [OR: 5.79 (1.70–19.13); p = 0.004] and diabetes mellitus [OR 5.86 (1.18–29.09); p = 0.03] with persistent albuminuria. Kaplan Meier analysis was consistent with a higher risk of decreased eGFR within 12 months for patients with albuminuria ≥30 mg/g (p = 0.02, logRank Test).

Conclusion

The incidence of HDP is increasing but most patients with HDP lack outpatient follow-up. In those with nephrological follow-up, decreased eGFR, evidence of CKD or residual hypertension are common. Metabolic conditions (obesity, diabetes mellitus) may identify those at higher risk of actionable short-term adverse kidney outcomes.

{"title":"Increasing incidence of hypertensive disorders of pregnancy and association with decreased GFR and albuminuria: The need for post-partum follow-up","authors":"Carolina Gracia-Iguacel , Manuel Pérez Torán , Miguel Alvaro Navidad , Begoña Gómez Pérez , José Miguel Arce-Obieta , Cristina Morocho-Pindo , Emilio González-Parra , Ignacio Mahillo , Alberto Ortiz","doi":"10.1016/j.placenta.2025.03.017","DOIUrl":"10.1016/j.placenta.2025.03.017","url":null,"abstract":"<div><h3>Background</h3><div>Hypertensive disorders of pregnancy (HDP) are associated with increased postpartum risk of cardiovascular disease or kidney failure. However, there is scarce information on the association with actionable kidney outcomes that should be treated to prevent progression to kidney failure.</div></div><div><h3>Objectives</h3><div>To evaluate the incidence of HDP over time and its association with kidney function, hypertension, and albuminuria during follow-up after discharge.</div></div><div><h3>Methods</h3><div>Single center retrospective cohort study of women without previous history of CKD among 20484 deliveries over 10 years.</div></div><div><h3>Results</h3><div>From 2008 to 2017, HDP was diagnosed in 846 (4.13 %) pregnant women. The incidence increased over time and was higher in women from Africa and America than in European women. The Nephrology department evaluated 210 (27 %) women with HDP during hospitalization and 170 (21 %) during follow-up. At follow-up, 5.3 % of the 150 women with available follow-up eGFR data had decreased eGFR (<90 ml/min/1.73 m<sup>2</sup>), 16.1 % albuminuria ≥30 mg/g and 8.6 % persistent hypertension. In multivariate analysis, gestational diabetes mellitus [OR 8.03 (95 % CI: 1.49–43.13; p 0.01)] and higher number of pregnancies [OR: 1.27 (95 % CI: 1.00–1.62; p 0.04)] were associated with persistent hypertension; diabetes mellitus [OR 14.07 (1.59–123.89); p = 0.02] with decreased glomerular filtration rate; and obesity [OR: 5.79 (1.70–19.13); p = 0.004] and diabetes mellitus [OR 5.86 (1.18–29.09); p = 0.03] with persistent albuminuria. Kaplan Meier analysis was consistent with a higher risk of decreased eGFR within 12 months for patients with albuminuria ≥30 mg/g (p = 0.02, logRank Test).</div></div><div><h3>Conclusion</h3><div>The incidence of HDP is increasing but most patients with HDP lack outpatient follow-up. In those with nephrological follow-up, decreased eGFR, evidence of CKD or residual hypertension are common. Metabolic conditions (obesity, diabetes mellitus) may identify those at higher risk of actionable short-term adverse kidney outcomes.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"165 ","pages":"Pages 42-49"},"PeriodicalIF":3.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143799412","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

Metformin ameliorates trophoblastic immunometabolic disorders via attenuating TLR4/NF-κB signaling through ATXN7L3-mediated histone H2B monoubiquitination

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-03-31 DOI: 10.1016/j.placenta.2025.03.020

Yang Zhang , Zhicheng Yu , Yin Zhao , Li Zou , Bin Deng , Xiaoxia Liu

Background

Trophoblastic inflammation and glycometabolic reprogramming represent two hallmarks of numerous diverse placental disorders, including but not limited to preterm labor, preeclampsia, and fetal growth restriction. Recent evidence indicates that TLR4/NF-κB signaling mediate the interaction between trophoblastic inflammation and glycometabolism disturbance while pharmacologic doses of metformin (MET, 10 μM) corrected these vicious states via its suppression on this pathway. However, the underlying precise mechanism remain incompletely understood.

Methods

ATXN7L3 was identified through comprehensive proteomic screening. The oxidative phosphorylation and glycolysis were detected to evaluate the metabolic reprogramming. ELISA and adhesion experiment were used to evaluate the trophoblastic inflammation. Chromatin immunoprecipitation assay and co-immunoprecipitation assays were used to clarify the precise mechanism of MET on TLR4/NF-κB signaling.

Results

MET corrected trophoblastic glycometabolic reprogramming and attenuated excessive inflammation via ATXN7L3. Mechanistically, MET regulated the TLR4/NF-κB signaling pathway through ATXN7L3-mediated Histone H2B monoubiquitylation.

Conclusions

Our findings elucidate a novel epigenetic regulatory mechanism whereby pharmacologic doses of MET ameliorated the TLR4/NF-κB signaling-induced immunometabolic disorders in trophoblasts through ATXN7L3-mediated H2Bub1. This study exploratively elucidated a novel mechanism underlying MET's pharmacological effects and provided novel insights into its role in ameliorating placental immunometabolism and development, potentially offering a novel pharmacological strategy for treating preeclampsia, fetal growth restriction, and related obstetrical syndromes.

{"title":"Metformin ameliorates trophoblastic immunometabolic disorders via attenuating TLR4/NF-κB signaling through ATXN7L3-mediated histone H2B monoubiquitination","authors":"Yang Zhang , Zhicheng Yu , Yin Zhao , Li Zou , Bin Deng , Xiaoxia Liu","doi":"10.1016/j.placenta.2025.03.020","DOIUrl":"10.1016/j.placenta.2025.03.020","url":null,"abstract":"<div><h3>Background</h3><div>Trophoblastic inflammation and glycometabolic reprogramming represent two hallmarks of numerous diverse placental disorders, including but not limited to preterm labor, preeclampsia, and fetal growth restriction. Recent evidence indicates that TLR4/NF-κB signaling mediate the interaction between trophoblastic inflammation and glycometabolism disturbance while pharmacologic doses of metformin (MET, 10 μM) corrected these vicious states via its suppression on this pathway. However, the underlying precise mechanism remain incompletely understood.</div></div><div><h3>Methods</h3><div>ATXN7L3 was identified through comprehensive proteomic screening. The oxidative phosphorylation and glycolysis were detected to evaluate the metabolic reprogramming. ELISA and adhesion experiment were used to evaluate the trophoblastic inflammation. Chromatin immunoprecipitation assay and co-immunoprecipitation assays were used to clarify the precise mechanism of MET on TLR4/NF-κB signaling.</div></div><div><h3>Results</h3><div>MET corrected trophoblastic glycometabolic reprogramming and attenuated excessive inflammation via ATXN7L3. Mechanistically, MET regulated the TLR4/NF-κB signaling pathway through ATXN7L3-mediated Histone H2B monoubiquitylation.</div></div><div><h3>Conclusions</h3><div>Our findings elucidate a novel epigenetic regulatory mechanism whereby pharmacologic doses of MET ameliorated the TLR4/NF-κB signaling-induced immunometabolic disorders in trophoblasts through ATXN7L3-mediated H2Bub1. This study exploratively elucidated a novel mechanism underlying MET's pharmacological effects and provided novel insights into its role in ameliorating placental immunometabolism and development, potentially offering a novel pharmacological strategy for treating preeclampsia, fetal growth restriction, and related obstetrical syndromes.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"165 ","pages":"Pages 50-61"},"PeriodicalIF":3.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143799997","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

Association of (TG)n(GA)m repeats downstream CMA1 gene with preeclampsia in Mexican population.

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-03-28 DOI: 10.1016/j.placenta.2025.03.018

L J Barragán-Zúñiga, M Sosa-Macias, L E Simental-Mendía, J Barragán-Zúñiga, B P Lazalde-Ramos, S Beltrán-Ontiveros, C Galaviz-Hernandez

Preeclampsia is a leading cause of maternal and fetal complications, often associated with endothelial dysfunction. Chymase, a proteolytic enzyme encoded by the CMA1 gene, has emerged as a potential contributor to this dysfunction. Although most preeclampsia (PE) studies have focused on maternal genetic factors, the role of paternal genetics remains underexamined. This study aimed to evaluate the association between the -1903 G/A SNV (rs1800875) and (TG)n(GA)m repeats downstream of the CMA1 gene with preeclampsia in pregnant women and their partners. A cross-sectional study was conducted involving women with PE, healthy pregnant women (HPW), and their corresponding partners, with genotyping, gene expression, and circulating protein levels assessed. A total of 141 participants were included, divided into preeclampsia (n = 80) and HPW (n = 61) groups. Women with PE showed significantly lower gestational age and higher recurrence of preeclampsia history compared to HPW. No significant association was found between the rs1800875 variant and preeclampsia; however, the (TG)n(GA)m repeat downstream of CMA1 gene was significantly associated with PE in women. Additionally, elevated serum IgE levels were significantly associated with preeclampsia (OR = 0.990; 95 % CI:0.983-0.998, p = 0.01). These findings suggest a possible role of polymorphic repeats in CMA1 as susceptibility factors for preeclampsia, indicating that both maternal and paternal genetic variations may contribute to the risk of this condition.

{"title":"Association of (TG)n(GA)m repeats downstream CMA1 gene with preeclampsia in Mexican population.","authors":"L J Barragán-Zúñiga, M Sosa-Macias, L E Simental-Mendía, J Barragán-Zúñiga, B P Lazalde-Ramos, S Beltrán-Ontiveros, C Galaviz-Hernandez","doi":"10.1016/j.placenta.2025.03.018","DOIUrl":"https://doi.org/10.1016/j.placenta.2025.03.018","url":null,"abstract":"<p><p>Preeclampsia is a leading cause of maternal and fetal complications, often associated with endothelial dysfunction. Chymase, a proteolytic enzyme encoded by the CMA1 gene, has emerged as a potential contributor to this dysfunction. Although most preeclampsia (PE) studies have focused on maternal genetic factors, the role of paternal genetics remains underexamined. This study aimed to evaluate the association between the -1903 G/A SNV (rs1800875) and (TG)n(GA)m repeats downstream of the CMA1 gene with preeclampsia in pregnant women and their partners. A cross-sectional study was conducted involving women with PE, healthy pregnant women (HPW), and their corresponding partners, with genotyping, gene expression, and circulating protein levels assessed. A total of 141 participants were included, divided into preeclampsia (n = 80) and HPW (n = 61) groups. Women with PE showed significantly lower gestational age and higher recurrence of preeclampsia history compared to HPW. No significant association was found between the rs1800875 variant and preeclampsia; however, the (TG)n(GA)m repeat downstream of CMA1 gene was significantly associated with PE in women. Additionally, elevated serum IgE levels were significantly associated with preeclampsia (OR = 0.990; 95 % CI:0.983-0.998, p = 0.01). These findings suggest a possible role of polymorphic repeats in CMA1 as susceptibility factors for preeclampsia, indicating that both maternal and paternal genetic variations may contribute to the risk of this condition.</p>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811855","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

Low level of lactate and trophoblast dysfunction mediated by SNAI1/PDK1 contributes to miscarriage 由 SNAI1/PDK1 介导的低乳酸水平和滋养细胞功能障碍导致流产

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-03-27 DOI: 10.1016/j.placenta.2025.03.022

Rui Gou , Fu-Fen Yin , Tian-Tian Han , Xiu-Ju Yin , Xue Zhong , Xiao-Hong Zhang

Introduction

Although the significance of metabolic remodelling in maintaining homeostasis at the maternal–foetal interface has been established, research on its implications in miscarriage remains limited.

Methods

Immunofluorescence, qRT-PCR, and western blotting were used to detect the expression of SNAI1 in miscarriage and normal villi. The function of the zinc-finger transcription factor SNAI1 was evaluated in three-dimensional (3D) trophoblast spheroids. Lactate production assays and western blotting were performed to investigate the effect of SNAI1 on lactate production and pyruvate dehydrogenase kinase 1 (PDK1) expression. Immunofluorescence and western blotting were used to detect the effect of lactate on SNAI1 expression. Furthermore, the role of PDK1 in miscarriage was confirmed in clinical samples.

Results

The expression of SNAI1 is significantly downregulated in the villi of patients with miscarriages. SNAI1 promotes proliferation, invasion, and inhibits apoptosis of HTR8/SVneo 3D spheroids. The glycolytic enzyme PDK1 has been identified as a downstream target of SNAI1 and plays a crucial role in regulating lactate production in trophoblasts. Lactate upregulates SNAI1 expression and promotes its nuclear localisation. Furthermore, the expression of PDK1 was downregulated in the villi of patients with miscarriage.

Discussion

Trophoblast spheroids may serve as reliable models to investigate the placenta. The regulatory mechanisms mediated by SNAI1/PDK1 in miscarriage have been elucidated. We provide new clues regarding the mechanism of miscarriage from a metabolic perspective and present evidence supporting lactate as a potential diagnostic marker.

{"title":"Low level of lactate and trophoblast dysfunction mediated by SNAI1/PDK1 contributes to miscarriage","authors":"Rui Gou , Fu-Fen Yin , Tian-Tian Han , Xiu-Ju Yin , Xue Zhong , Xiao-Hong Zhang","doi":"10.1016/j.placenta.2025.03.022","DOIUrl":"10.1016/j.placenta.2025.03.022","url":null,"abstract":"<div><h3>Introduction</h3><div>Although the significance of metabolic remodelling in maintaining homeostasis at the maternal–foetal interface has been established, research on its implications in miscarriage remains limited.</div></div><div><h3>Methods</h3><div>Immunofluorescence, qRT-PCR, and western blotting were used to detect the expression of SNAI1 in miscarriage and normal villi. The function of the zinc-finger transcription factor SNAI1 was evaluated in three-dimensional (3D) trophoblast spheroids. Lactate production assays and western blotting were performed to investigate the effect of SNAI1 on lactate production and pyruvate dehydrogenase kinase 1 (PDK1) expression. Immunofluorescence and western blotting were used to detect the effect of lactate on SNAI1 expression. Furthermore, the role of PDK1 in miscarriage was confirmed in clinical samples.</div></div><div><h3>Results</h3><div>The expression of SNAI1 is significantly downregulated in the villi of patients with miscarriages. SNAI1 promotes proliferation, invasion, and inhibits apoptosis of HTR8/SVneo 3D spheroids. The glycolytic enzyme PDK1 has been identified as a downstream target of SNAI1 and plays a crucial role in regulating lactate production in trophoblasts. Lactate upregulates SNAI1 expression and promotes its nuclear localisation. Furthermore, the expression of PDK1 was downregulated in the villi of patients with miscarriage.</div></div><div><h3>Discussion</h3><div>Trophoblast spheroids may serve as reliable models to investigate the placenta. The regulatory mechanisms mediated by SNAI1/PDK1 in miscarriage have been elucidated. We provide new clues regarding the mechanism of miscarriage from a metabolic perspective and present evidence supporting lactate as a potential diagnostic marker.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"165 ","pages":"Pages 33-41"},"PeriodicalIF":3.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777492","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}

引用次数: 0

Analysis of drug transporter expression in syncytiotrophoblast derived from human placental stem cells: Expression and function of efflux transporters

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-03-27 DOI: 10.1016/j.placenta.2025.03.021

Riko Sawada , Ayako Furugen , Ayami Ueda , Ayako Nishimura , Takeshi Umazume , Katsuya Narumi , Masaki Kobayashi

Objective

The placenta is a vital organ for exchanging nutrients, endogenous substances, and xenobiotics between mother and fetus. The syncytiotrophoblast (ST) is crucial in maintaining the placental barrier. Human trophoblast stem cells (hTSCs) have been recently established; however, their utility in studying placental transport functions has not been fully elucidated. This study investigated the expression and function of transporters in hTSC-derived ST cells.

Methods

TS^CT cells, as hTSCs, were differentiated into ST-like cells (ST-TS^CT), and the gene expression of 84 transporters in ST-TS^CT cells was evaluated using a PCR array. BeWo cells, a widely used trophoblast model, were used for comparison. BeWo cells were differentiated into ST-like cells using forskolin [BeWo (FK)]. The protein levels of efflux transporters were examined by western blotting, and functional assays were performed using typical fluorescent substrates.

Results

Transporter gene expression levels were higher in ST-TS^CT than in BeWo (FK) cells, with 27 genes showing more than a 3-fold increase. Ten of these genes were exclusively expressed in ST-TS^CT. Western blotting revealed the presence of efflux transporters, including P-glycoprotein (P-gp/ABCB1), breast cancer resistance protein (BCRP/ABCG2), and multidrug resistance-associated protein 2 (MRP2/ABCC2). Furthermore, the accumulation of typical substrates (Rhodamine123 for P-gp, Hoechst33342 and BODIPY™ FL Prazosin for BCRP, and 5(6)-carboxy-2′,7′-dichlorofluorescein diacetate for MRP) significantly increased when transporter inhibitors (elacridar, Ko143, and MK571) were applied.

Conclusion

This study showed higher transporter expression in ST-TS^CT than that in a traditional trophoblast model. Furthermore, the functional expression of efflux transporters was observed. ST-TS^CT is valuable for investigating placental transport functions.

{"title":"Analysis of drug transporter expression in syncytiotrophoblast derived from human placental stem cells: Expression and function of efflux transporters","authors":"Riko Sawada , Ayako Furugen , Ayami Ueda , Ayako Nishimura , Takeshi Umazume , Katsuya Narumi , Masaki Kobayashi","doi":"10.1016/j.placenta.2025.03.021","DOIUrl":"10.1016/j.placenta.2025.03.021","url":null,"abstract":"<div><h3>Objective</h3><div>The placenta is a vital organ for exchanging nutrients, endogenous substances, and xenobiotics between mother and fetus. The syncytiotrophoblast (ST) is crucial in maintaining the placental barrier. Human trophoblast stem cells (hTSCs) have been recently established; however, their utility in studying placental transport functions has not been fully elucidated. This study investigated the expression and function of transporters in hTSC-derived ST cells.</div></div><div><h3>Methods</h3><div>TS<sup>CT</sup> cells, as hTSCs, were differentiated into ST-like cells (ST-TS<sup>CT</sup>), and the gene expression of 84 transporters in ST-TS<sup>CT</sup> cells was evaluated using a PCR array. BeWo cells, a widely used trophoblast model, were used for comparison. BeWo cells were differentiated into ST-like cells using forskolin [BeWo (FK)]. The protein levels of efflux transporters were examined by western blotting, and functional assays were performed using typical fluorescent substrates.</div></div><div><h3>Results</h3><div>Transporter gene expression levels were higher in ST-TS<sup>CT</sup> than in BeWo (FK) cells, with 27 genes showing more than a 3-fold increase. Ten of these genes were exclusively expressed in ST-TS<sup>CT</sup>. Western blotting revealed the presence of efflux transporters, including P-glycoprotein (P-gp/<em>ABCB1</em>), breast cancer resistance protein (BCRP/<em>ABCG2</em>), and multidrug resistance-associated protein 2 (MRP2/<em>ABCC2</em>). Furthermore, the accumulation of typical substrates (Rhodamine123 for P-gp, Hoechst33342 and BODIPY™ FL Prazosin for BCRP, and 5(6)-carboxy-2′,7′-dichlorofluorescein diacetate for MRP) significantly increased when transporter inhibitors (elacridar, Ko143, and MK571) were applied.</div></div><div><h3>Conclusion</h3><div>This study showed higher transporter expression in ST-TS<sup>CT</sup> than that in a traditional trophoblast model. Furthermore, the functional expression of efflux transporters was observed. ST-TS<sup>CT</sup> is valuable for investigating placental transport functions.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"165 ","pages":"Pages 23-32"},"PeriodicalIF":3.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143769282","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}

引用次数: 0