International Journal of Molecular Sciences

Editorial

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Open AccessEditorial

Placental Related Disorders of Pregnancy 2.0

by Eun D. Lee and Hiten D. Mistry

Int. J. Mol. Sci. 2023, 24(18), 14286; https://doi.org/10.3390/ijms241814286 - 19 Sep 2023

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Abstract

Following our first Special Issue, we are pleased to present this Special Issue in the International Journal of Molecular Sciences entitled ‘Placental Related Disorders of Pregnancy 2 [...] Full article

(This article belongs to the Special Issue Placental Related Disorders of Pregnancy 2.0.)

Research

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12 pages, 3208 KiB

Open AccessArticle

MIF Increases sFLT1 Expression in Early Uncomplicated Pregnancy and Preeclampsia

by Qing Yong, Kyra L. Dijkstra, Carin van der Keur, Jan A. Bruijn, Michael Eikmans and Hans J. Baelde

Int. J. Mol. Sci. 2023, 24(12), 10050; https://doi.org/10.3390/ijms241210050 - 13 Jun 2023

Cited by 3 | Viewed by 1087

Abstract

Insufficient immune tolerance during pregnancy is associated with pathological conditions such as preeclampsia (PE). Soluble fms-like tyrosine kinase-1 (sFLT1), which exerts a role in the late stage of PE, has shown its beneficial anti-inflammatory effects in inflammation-associated diseases. Macrophage migration inhibitory factor (MIF) [...] Read more.

Insufficient immune tolerance during pregnancy is associated with pathological conditions such as preeclampsia (PE). Soluble fms-like tyrosine kinase-1 (sFLT1), which exerts a role in the late stage of PE, has shown its beneficial anti-inflammatory effects in inflammation-associated diseases. Macrophage migration inhibitory factor (MIF) was reported to upregulate sFLT1 production in experimental congenital diaphragmatic hernia. However, the placental sFLT1 expression in early uncomplicated pregnancy and whether MIF can regulate sFLT1 expression in uncomplicated and preeclamptic pregnancy are unclear. We collected first-trimester placentas and term placentas from uncomplicated and preeclamptic pregnancies to investigate sFLT1 and MIF expression in vivo. Primary cytotrophoblasts (CTBs) and a human trophoblast cell line (Bewo) were used to study the regulation of MIF on sFLT1 expression in vitro. In placentas from first-trimester pregnancy, we observed a high expression of sFLT1, specifically in extravillous trophoblasts (EVTs) and syncytiotrophoblast (STB) cells. MIF mRNA levels strongly correlated with sFLT1 expression in term placentas from preeclamptic pregnancies. In in vitro experiments, sFLT1 and MIF levels increased significantly in CTBs during their differentiation to EVTs and STBs, and MIF inhibitor (ISO-1) significantly reduced sFLT1 expression in a dose-dependent manner during this process. sFLT1 showed significant upregulation with increasing doses of MIF in Bewo cells. Our results show that sFLT1 is highly expressed at the maternal–fetal interface during early pregnancy and that MIF can increase sFLT1 expression in early uncomplicated pregnancy and PE, which suggests that sFLT1 plays an essential role in the modulation of inflammation in pregnancy. Full article

(This article belongs to the Special Issue Placental Related Disorders of Pregnancy 2.0.)

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10 pages, 2472 KiB

Open AccessCommunication

Kisspeptin Suppresses Inflammasome-NLRP3 Activation and Pyroptosis Caused by Hypothyroidism at the Maternal-Fetal Interface of Rats

by Bianca Reis Santos, Jeane Martinha dos Anjos Cordeiro, Luciano Cardoso Santos, Larissa da Silva Santana, Acácia Eduarda de Jesus Nascimento and Juneo Freitas Silva

Int. J. Mol. Sci. 2023, 24(7), 6820; https://doi.org/10.3390/ijms24076820 - 06 Apr 2023

Cited by 5 | Viewed by 1510

Abstract

Gestational diseases such as preeclampsia and gestational diabetes cause inflammasome activation and pyroptosis in the placenta and changes in placental kisspeptin levels. Although maternal hypothyroidism also reduces the kisspeptin/Kiss1R system at the maternal-fetal interface, there is still no information on whether this dysfunction [...] Read more.

Gestational diseases such as preeclampsia and gestational diabetes cause inflammasome activation and pyroptosis in the placenta and changes in placental kisspeptin levels. Although maternal hypothyroidism also reduces the kisspeptin/Kiss1R system at the maternal-fetal interface, there is still no information on whether this dysfunction causes inflammasome activation and pyroptosis in the placenta or influences the modulatory role of kisspeptin in these processes. This study aimed to evaluate whether hypothyroidism activates the inflammasome-NLRP3 pathway and pyroptosis at the maternal-fetal interface of rats and whether kisspeptin can modulate these processes. Hypothyroidism was induced in Wistar rats by the administration of propylthiouracil. Kisspeptin-10 (Kp10) treatment began on the 8th day of gestation (DG). Gene and/or protein expressions of NLRP3, Caspase 1, IL-1β, IL-18, and Gasdermin D (Gsmd) were evaluated in the deciduae and placentae at the 18th DG. Hypothyroidism increased the decidual and placental stainings of NLRP3, IL-1β, and Gasdermin D, and increased the gene expressions of Nlrp3, Ilβ, and Il18 in the placenta and of Gsmd in the decidua. Treatment with Kp10 suppressed the increase in NLRP3/Nlrp3, IL-1β, Il18, and Gasdermin D/Gsmd caused by hypothyroidism at the maternal-fetal interface. However, Kp10 increased the placental gene expressions of Casp1 and Il1β. The findings demonstrated that maternal hypothyroidism activated the inflammasome-NLRP3 pathway and pyroptosis at the maternal-fetal interface of rats and that treatment with Kp10 was able to block these processes, thus suggesting that kisspeptin analogues may be promising in the treatment of gestational diseases that involve inflammasome activation and pyroptosis. Full article

(This article belongs to the Special Issue Placental Related Disorders of Pregnancy 2.0.)

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16 pages, 2561 KiB

Open AccessArticle

Alterations in Antioxidant Micronutrient Concentrations in Placental Tissue, Maternal Blood and Urine and the Fetal Circulation in Pre-eclampsia

by Lesia O. Kurlak, Paula J. Scaife, Louise V. Briggs, Fiona Broughton Pipkin, David S. Gardner and Hiten D. Mistry

Int. J. Mol. Sci. 2023, 24(4), 3579; https://doi.org/10.3390/ijms24043579 - 10 Feb 2023

Cited by 4 | Viewed by 1458

Abstract

Trace elements such as selenium and zinc are vital components of many enzymes, including endogenous antioxidants, and can interact with each other. Women with pre-eclampsia, the hypertensive disease of pregnancy, have been reported as having changes in some individual antioxidant trace elements during [...] Read more.

Trace elements such as selenium and zinc are vital components of many enzymes, including endogenous antioxidants, and can interact with each other. Women with pre-eclampsia, the hypertensive disease of pregnancy, have been reported as having changes in some individual antioxidant trace elements during pregnancy, which are related to maternal and fetal mortality and morbidity. We hypothesised that examination of the three compartments of (a) maternal plasma and urine, (b) placental tissue and (c) fetal plasma in normotensive and hypertensive pregnant women would allow identification of biologically significant changes and interactions in selenium, zinc, manganese and copper. Furthermore, these would be related to changes in the angiogenic markers, placental growth factor (PlGF) and Soluble Fms-Like Tyrosine Kinase-1 (sFlt-1) concentrations. Venous plasma and urine were collected from healthy non-pregnant women (n = 30), normotensive pregnant controls (n = 60) and women with pre-eclampsia (n = 50) in the third trimester. Where possible, matched placental tissue samples and umbilical venous (fetal) plasma were also collected. Antioxidant micronutrient concentrations were measured by inductively coupled plasma mass-spectrometry. Urinary levels were normalised to creatinine concentration. Plasma active PlGF and sFlt-1 concentrations were measured by ELISA. Maternal plasma selenium, zinc and manganese were all lower in women with pre-eclampsia (p < 0.05), as were fetal plasma selenium and manganese (p < 0.05 for all); maternal urinary concentrations were lower for selenium and zinc (p < 0.05). Conversely, maternal and fetal plasma and urinary copper concentrations were higher in women with pre-eclampsia (p < 0.05). Differences in placental concentrations varied, with lower overall levels of selenium and zinc (p < 0.05) in women with pre-eclampsia. Maternal and fetal PlGF were lower and sFlt-1 higher in women with pre-eclampsia; maternal plasma zinc was positively correlated with maternal plasma sFlt-1 (p < 0.05). Because of perceptions that early- and late-onset pre-eclampsia have differing aetiologies, we subdivided maternal and fetal data accordingly. No major differences were observed, but fetal sample sizes were small following early-onset. Disruption in these antioxidant micronutrients may be responsible for some of the manifestations of pre-eclampsia, including contributing to an antiangiogenic state. The potential benefits of mineral supplementation, in women with deficient intakes, during pregnancy to reduce pre-eclampsia remain an important area for experimental and clinical research. Full article

(This article belongs to the Special Issue Placental Related Disorders of Pregnancy 2.0.)

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16 pages, 2083 KiB

Open AccessArticle

Heterogenous Differences in Cellular Senescent Phenotypes in Pre-Eclampsia and IUGR following Quantitative Assessment of Multiple Biomarkers of Senescence

by Samprikta Manna, Colm J. Mc Elwain, Gillian M. Maher, Marta Giralt Martín, Andrea Musumeci, Fergus P. McCarthy and Cathal McCarthy

Int. J. Mol. Sci. 2023, 24(4), 3101; https://doi.org/10.3390/ijms24043101 - 04 Feb 2023

Cited by 1 | Viewed by 1585

Abstract

Premature ageing of the placenta in pregnancy outcomes is associated with the persistent presence of oxidative stress and placental insufficiency reducing its functional capacity. In this study, we investigated cellular senescence phenotypes of pre-eclampsia and IUGR pregnancies by simultaneously measuring several biomarkers of [...] Read more.

Premature ageing of the placenta in pregnancy outcomes is associated with the persistent presence of oxidative stress and placental insufficiency reducing its functional capacity. In this study, we investigated cellular senescence phenotypes of pre-eclampsia and IUGR pregnancies by simultaneously measuring several biomarkers of senescence. Maternal plasma and placental samples were collected at term gestation from nulliparous women undergoing pre-labour elective caesarean section with pre-eclampsia without intrauterine growth restriction (PE; n = 5), pre-eclampsia associated with intrauterine growth restriction (n = 8), intrauterine growth restriction (IUGR < 10th centile; n = 6), and age-matched controls (n = 20). Placental absolute telomere length and senescence gene analysis was performed by RTqPCR. The expression of cyclin-dependent kinase inhibitors (p21 and p16) was determined by Western blot. Senescence-associated secretory phenotypes (SASPs) were evaluated in maternal plasma by multiplex ELISA assay. Placental expression of senescence-associated genes showed significant increases in CHEK1, PCNA, PTEN, CDKN2A, and CCNB-1 (p < 0.05) in pre-eclampsia, while TBX-2, PCNA, ATM, and CCNB-1 expression were evident (p < 0.05) and were significantly decreased in IUGR compared with controls. Placental p16 protein expression was significantly decreased in pre-eclampsia only compared with controls (p = 0.028). IL-6 was significantly increased in pre-eclampsia (0.54 pg/mL ± 0.271 vs. 0.3 pg/mL ± 0.102; p = 0.017) while IFN-γ was significantly increased in IUGR (4.6 pg/mL ± 2.2 vs. 2.17 pg/mL ± 0.8; p = 0.002) compared with controls. These results provide evidence of premature senescence in IUGR pregnancies, and while cell cycle checkpoint regulators are activated in pre-eclampsia, the cellular phenotype is one of cell repair and subsequent proliferation rather than progression to senescence. The heterogeneity of these cellular phenotypes highlights the complexity of characterising cellular senescence and may equally be indicative of the differing pathophysiological insults unique to each obstetric complication. Full article

(This article belongs to the Special Issue Placental Related Disorders of Pregnancy 2.0.)

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16 pages, 2101 KiB

Open AccessArticle

The Blocking of Integrin-Mediated Interactions with Maternal Endothelial Cells Reversed the Endothelial Cell Dysfunction Induced by EVs, Derived from Preeclamptic Placentae

by Yourong Feng, Qi Chen, Sien Yee Lau, Bridget W. Tsai, Katie Groom, Carolyn J. Barrett and Lawrence W. Chamley

Int. J. Mol. Sci. 2022, 23(21), 13115; https://doi.org/10.3390/ijms232113115 - 28 Oct 2022

Cited by 7 | Viewed by 1471

Abstract

Placental extracellular vesicles (EVs) have increasingly been recognized as a major mediator of feto-maternal communication. However, the cellular and molecular mechanisms of the uptake of placental EVs by recipient cells are still not well-understood. We previously reported that placental EVs target a limited [...] Read more.

Placental extracellular vesicles (EVs) have increasingly been recognized as a major mediator of feto-maternal communication. However, the cellular and molecular mechanisms of the uptake of placental EVs by recipient cells are still not well-understood. We previously reported that placental EVs target a limited number of organs in vivo. In the current study, we investigated the mechanisms underlying the uptake of placental EVs into target cells. Placental EVs were derived from explant cultures of normal or preeclamptic placentae. The mechanisms underlying the uptake of placental EVs were elucidated, using the phagocytosis or endocytosis inhibitor, trypsin-treatment or integrin-blocking peptides. The endothelial cell activation was studied using the monocyte adhesion assay after the preeclamptic EVs exposure, with and/or without treatment with the integrin blocking peptide, YIGSR. The cellular mechanism of the uptake of the placental EVs was time, concentration and energy-dependent and both the phagocytosis and endocytosis were involved in this process. Additionally, proteins on the surface of the placental EVs, including integrins, were involved in the EV uptake process. Furthermore, inhibiting the uptake of preeclamptic EVs with YIGSR, reduced the endothelial cell activation. The interaction between the placental EVs and the recipient cells is mediated by integrins, and the cellular uptake is mediated by a combination of both phagocytosis and endocytosis. Full article

(This article belongs to the Special Issue Placental Related Disorders of Pregnancy 2.0.)

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Review

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10 pages, 471 KiB

Open AccessReview

Biomarkers for Pregnancy Latency Prediction after Preterm Premature Rupture of Membranes–A Systematic Review

by Stepan Feduniw, Michal Pruc, Michal Ciebiera, Natalia Zeber-Lubecka, Diana Massalska, Magdalena Zgliczynska, Agnieszka Pawlowska and Lukasz Szarpak

Int. J. Mol. Sci. 2023, 24(9), 8027; https://doi.org/10.3390/ijms24098027 - 28 Apr 2023

Cited by 2 | Viewed by 1937

Abstract

Preterm premature rupture of membranes, leading to preterm birth, is associated with neonatal and maternal morbidity and mortality. The study aimed to review the existing data on the best predictive value of pregnancy latency for known biomarkers in pregnancies after preterm premature rupture [...] Read more.

Preterm premature rupture of membranes, leading to preterm birth, is associated with neonatal and maternal morbidity and mortality. The study aimed to review the existing data on the best predictive value of pregnancy latency for known biomarkers in pregnancies after preterm premature rupture of membranes. The following databases were screened for the purposes of this systematic review: Pubmed/MEDLINE, Web of Science, EMBASE, Scopus, and the Cochrane Library. The study was conducted according to the PRISMA guidelines for systematic reviews. Only a few studies assessed biomarkers predicting pregnancy duration after PPROM. IL-6, IL-8, CRP, IL1RA, s-endoglin, βhCG, AFP, PCT, urea, creatinine, oxygen radical absorbance capacity, MDA, lipocalin-2, endotoxin activity, MMP-8, MMP-9 and S100 A8/A9 were found to have a positive predictive value for delivery timing prediction. Proinflammatory biomarkers, such as IL-6 or CRP, proved to be best correlated with delivery timing, independent of the occurrence of intrauterine infection. Full article

(This article belongs to the Special Issue Placental Related Disorders of Pregnancy 2.0.)

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20 pages, 1424 KiB

Open AccessReview

The Apelinergic System in Pregnancy

by Océane Pécheux, Ana Correia-Branco, Marie Cohen and Begoῆa Martinez de Tejada

Int. J. Mol. Sci. 2023, 24(9), 8014; https://doi.org/10.3390/ijms24098014 - 28 Apr 2023

Cited by 2 | Viewed by 1580

Abstract

The apelinergic system is a highly conserved pleiotropic system. It comprises the apelin receptor apelin peptide jejunum (APJ) and its two peptide ligands, Elabela/Toddler (ELA) and apelin, which have different spatiotemporal localizations. This system has been implicated in the regulation of the adipoinsular [...] Read more.

The apelinergic system is a highly conserved pleiotropic system. It comprises the apelin receptor apelin peptide jejunum (APJ) and its two peptide ligands, Elabela/Toddler (ELA) and apelin, which have different spatiotemporal localizations. This system has been implicated in the regulation of the adipoinsular axis, in cardiovascular and central nervous systems, in carcinogenesis, and in pregnancy in humans. During pregnancy, the apelinergic system is essential for embryo cardiogenesis and vasculogenesis and for placental development and function. It may also play a role in the initiation of labor. The apelinergic system seems to be involved in the development of placenta-related pregnancy complications, such as preeclampsia (PE) and intrauterine growth restriction, but an improvement in PE-like symptoms and birth weight has been described in murine models after the exogenous administration of apelin or ELA. Although the expression of ELA, apelin, and APJ is altered in human PE placenta, data related to their circulating levels are inconsistent. This article reviews current knowledge about the roles of the apelinergic system in pregnancy and its pathophysiological roles in placenta-related complications in pregnancy. We also discuss the challenges in translating the actors of the apelinergic system into a marker or target for therapeutic interventions in obstetrics. Full article

(This article belongs to the Special Issue Placental Related Disorders of Pregnancy 2.0.)

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22 pages, 2399 KiB

Open AccessReview

Biochemical Screening for Fetal Trisomy 21: Pathophysiology of Maternal Serum Markers and Involvement of the Placenta

by Jean Guibourdenche, Marie-Clémence Leguy, Guillaume Pidoux, Marylise Hebert-Schuster, Christelle Laguillier, Olivia Anselem, Gilles Grangé, Fidéline Bonnet and Vassilis Tsatsaris

Int. J. Mol. Sci. 2023, 24(8), 7669; https://doi.org/10.3390/ijms24087669 - 21 Apr 2023

Cited by 3 | Viewed by 4432

Abstract

It is now well established that maternal serum markers are often abnormal in fetal trisomy 21. Their determination is recommended for prenatal screening and pregnancy follow-up. However, mechanisms leading to abnormal maternal serum levels of such markers are still debated. Our objective was [...] Read more.

It is now well established that maternal serum markers are often abnormal in fetal trisomy 21. Their determination is recommended for prenatal screening and pregnancy follow-up. However, mechanisms leading to abnormal maternal serum levels of such markers are still debated. Our objective was to help clinicians and scientists unravel the pathophysiology of these markers via a review of the main studies published in this field, both in vivo and in vitro, focusing on the six most widely used markers (hCG, its free subunit hCGβ, PAPP-A, AFP, uE3, and inhibin A) as well as cell-free feto–placental DNA. Analysis of the literature shows that mechanisms underlying each marker’s regulation are multiple and not necessarily directly linked with the supernumerary chromosome 21. The crucial involvement of the placenta is also highlighted, which could be defective in one or several of its functions (turnover and apoptosis, endocrine production, and feto–maternal exchanges and transfer). These defects were neither constant nor specific for trisomy 21, and might be more or less pronounced, reflecting a high variability in placental immaturity and alteration. This explains why maternal serum markers can lack both specificity and sensitivity, and are thus restricted to screening. Full article

(This article belongs to the Special Issue Placental Related Disorders of Pregnancy 2.0.)

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17 pages, 709 KiB

Open AccessReview

SARS-CoV-2 Transplacental Transmission: A Rare Occurrence? An Overview of the Protective Role of the Placenta

by Yin Ping Wong, Geok Chin Tan and T. Yee Khong

Int. J. Mol. Sci. 2023, 24(5), 4550; https://doi.org/10.3390/ijms24054550 - 25 Feb 2023

Cited by 5 | Viewed by 2483

Abstract

The outbreak of the coronavirus disease 2019 (COVID-19) pandemic, caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global public health crisis, causing substantial concern especially to the pregnant population. Pregnant women infected with SARS-CoV-2 are at greater [...] Read more.

The outbreak of the coronavirus disease 2019 (COVID-19) pandemic, caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global public health crisis, causing substantial concern especially to the pregnant population. Pregnant women infected with SARS-CoV-2 are at greater risk of devastating pregnancy complications such as premature delivery and stillbirth. Irrespective of the emerging reported cases of neonatal COVID-19, reassuringly, confirmatory evidence of vertical transmission is still lacking. The protective role of the placenta in limiting in utero spread of virus to the developing fetus is intriguing. The short- and long-term impact of maternal COVID-19 infection in the newborn remains an unresolved question. In this review, we explore the recent evidence of SARS-CoV-2 vertical transmission, cell-entry pathways, placental responses towards SARS-CoV-2 infection, and its potential effects on the offspring. We further discuss how the placenta serves as a defensive front against SARS-CoV-2 by exerting various cellular and molecular defense pathways. A better understanding of the placental barrier, immune defense, and modulation strategies involved in restricting transplacental transmission may provide valuable insights for future development of antiviral and immunomodulatory therapies to improve pregnancy outcomes. Full article

(This article belongs to the Special Issue Placental Related Disorders of Pregnancy 2.0.)

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14 pages, 1430 KiB

Open AccessReview

Atypical Preeclampsia before 20 Weeks of Gestation—A Systematic Review

by Jan Modzelewski, Iga Siarkowska, Justyna Pajurek-Dudek, Stepan Feduniw, Katarzyna Muzyka-Placzyńska, Arkadiusz Baran, Anna Kajdy, Magdalena Bednarek-Jędrzejek, Aneta Cymbaluk-Płoska, Ewa Kwiatkowska and Sebastian Kwiatkowski

Int. J. Mol. Sci. 2023, 24(4), 3752; https://doi.org/10.3390/ijms24043752 - 13 Feb 2023

Cited by 9 | Viewed by 4162

Abstract

This systematic review was conducted to gather evidence of preeclampsia occurring before the 20th week of gestation, additionally considering the role of PLGF and sFlt-1 in the development of the disease. In the three cases of preeclampsia before the 20th week of gestation [...] Read more.

This systematic review was conducted to gather evidence of preeclampsia occurring before the 20th week of gestation, additionally considering the role of PLGF and sFlt-1 in the development of the disease. In the three cases of preeclampsia before the 20th week of gestation presented in the authors’ material, all pregnancies ended up with IUFD, and the SFlt-1/PLGF ratios were significantly elevated in all women. Eligible publications were identified with searches in the PubMed, Embase, Scopus, and Web of Science databases. No date or language restrictions were made. All original peer-reviewed scientific reports were included. A total of 30 publications were included in the final report, including case reports and case series. No other publication types regarding this issue were identified. In the literature, 34 cases of preeclampsia with onset occurring before the 20th week of gestation were identified, for a final total of 37 cases. Live births were reported in 5 cases (10.52%), and there were 9 intrauterine fetal demises (24.32%), and 23 terminations of pregnancy (62.16%). Preeclampsia before the 20th week of gestation is rare but can occur. We collected all available evidence regarding this phenomenon, with 37 cases reported worldwide. We call for large-scale cohort or register-based studies to establish revised definitions or develop new ones regarding the currently unrecognized very early onset preeclampsia. Full article

(This article belongs to the Special Issue Placental Related Disorders of Pregnancy 2.0.)

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16 pages, 323 KiB

Open AccessReview

A Comparative Review of Pregnancy and Cancer and Their Association with Endoplasmic Reticulum Aminopeptidase 1 and 2

by Brian Hur, Veronica Wong and Eun D. Lee

Int. J. Mol. Sci. 2023, 24(4), 3454; https://doi.org/10.3390/ijms24043454 - 09 Feb 2023

Cited by 3 | Viewed by 2004

Abstract

The fundamental basis of pregnancy and cancer is to determine the fate of the survival or the death of humanity. However, the development of fetuses and tumors share many similarities and differences, making them two sides of the same coin. This review presents [...] Read more.

The fundamental basis of pregnancy and cancer is to determine the fate of the survival or the death of humanity. However, the development of fetuses and tumors share many similarities and differences, making them two sides of the same coin. This review presents an overview of the similarities and differences between pregnancy and cancer. In addition, we will also discuss the critical roles that Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and 2 may play in the immune system, cell migration, and angiogenesis, all of which are essential for fetal and tumor development. Even though the comprehensive understanding of ERAP2 lags that of ERAP1 due to the lack of an animal model, recent studies have shown that both enzymes are associated with an increased risk of several diseases, including pregnancy disorder pre-eclampsia (PE), recurrent miscarriages, and cancer. The exact mechanisms in both pregnancy and cancer need to be elucidated. Therefore, a deeper understanding of ERAP’s role in diseases can make it a potential therapeutic target for pregnancy complications and cancer and offer greater insight into its impact on the immune system. Full article

(This article belongs to the Special Issue Placental Related Disorders of Pregnancy 2.0.)

25 pages, 1386 KiB

Open AccessReview

Reliability of Rodent and Rabbit Models in Preeclampsia Research

by Agata Sakowicz, Michalina Bralewska, Piotr Kamola and Tadeusz Pietrucha

Int. J. Mol. Sci. 2022, 23(22), 14344; https://doi.org/10.3390/ijms232214344 - 18 Nov 2022

Cited by 4 | Viewed by 2455

Abstract

In vivo studies on the pathology of gestation, including preeclampsia, often use small mammals such as rabbits or rodents, i.e., mice, rats, hamsters, and guinea pigs. The key advantage of these animals is their short reproductive cycle; in addition, similar to humans, they [...] Read more.

In vivo studies on the pathology of gestation, including preeclampsia, often use small mammals such as rabbits or rodents, i.e., mice, rats, hamsters, and guinea pigs. The key advantage of these animals is their short reproductive cycle; in addition, similar to humans, they also develop a haemochorial placenta and present a similar transformation of maternal spiral arteries. Interestingly, pregnant dams also demonstrate a similar reaction to inflammatory factors and placentally derived antiangiogenic factors, i.e., soluble fms-like tyrosine kinase 1 (sFlt-1) or soluble endoglin-1 (sEng), as preeclamptic women: all animals present an increase in blood pressure and usually proteinuria. These constitute the classical duet that allows for the recognition of preeclampsia. However, the time of initiation of maternal vessel remodelling and the depth of trophoblast invasion differs between rabbits, rodents, and humans. Unfortunately, at present, no known animal replicates a human pregnancy exactly, and hence, the use of rabbit and rodent models is restricted to the investigation of individual aspects of human gestation only. This article compares the process of placentation in rodents, rabbits, and humans, which should be considered when planning experiments on preeclampsia; these aspects might determine the success, or failure, of the study. The report also reviews the rodent and rabbit models used to investigate certain aspects of the pathomechanism of human preeclampsia, especially those related to incorrect trophoblast invasion, placental hypoxia, inflammation, or maternal endothelial dysfunction. Full article

(This article belongs to the Special Issue Placental Related Disorders of Pregnancy 2.0.)

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