Spiral Artery Remodeling Research Articles

Estrogen Actions in Placental Vascular Morphogenesis and Spiral Artery Remodeling: A Comparative View between Humans and Mice.

Estrogens, mainly 17β-estradiol (E2), play a critical role in reproductive organogenesis, ovulation, and fertility via estrogen receptors. E2 is also a well-known regulator of utero-placental vascular development and blood-flow dynamics throughout gestation. Mouse and human placentas possess strikingly different morphological configurations that confer important reproductive advantages. However, the functional interplay between fetal and maternal vasculature remains similar in both species. In this review, we briefly describe the structural and functional characteristics, as well as the development, of mouse and human placentas. In addition, we summarize the current knowledge regarding estrogen actions during utero-placental vascular morphogenesis, which includes uterine angiogenesis, the control of trophoblast behavior, spiral artery remodeling, and hemodynamic adaptation throughout pregnancy, in both mice and humans. Finally, the estrogens that are present in abnormal placentation are also mentioned. Overall, this review highlights the importance of the actions of estrogens in the physiology and pathophysiology of placental vascular development.

The central role of natural killer cells in preeclampsia.

Preeclampsia (PE) is a disease that is unique to pregnancy and affects multiple systems. It can lead to maternal and perinatal mortality. The precise etiology of PE is unclear. Patients with PE may have systemic or local immune abnormalities. A group of researchers has proposed that the immune communication between the fetus and mother is primarily moderated by natural killer (NK) cells as opposed to T cells, since NK cells are the most abundant immune cells in the uterus. This review examines the immunological roles of NK cells in the pathogenesis of PE. Our aim is to provide obstetricians with a comprehensive and updated research progress report on NK cells in PE patients. It has been reported that decidual NK (dNK) cells contribute to the process of uterine spiral artery remodeling and can modulate trophoblast invasion. Additionally, dNK cells can stimulate fetal growth and regulate delivery. It appears that the count or proportion of circulating NK cells is elevated in patients with or at risk for PE. Changes in the number or function of dNK cells may be the cause of PE. The Th1/Th2 equilibrium in PE has gradually shifted to an NK1/NK2 equilibrium based on cytokine production. An improper combination of killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA)-C may lead to insufficient activation of dNK cells, thereby causing PE. In the etiology of PE, NK cells appear to exert a central effect in both peripheral blood and the maternal-fetal interface. To maintain immune equilibrium both locally and systemically, it is necessary to take therapeutic measures directed at NK cells.

Perspectives on the Use of Placental Growth Factor (PlGF) in the Prediction and Diagnosis of Pre-Eclampsia: Recent Insights and Future Steps.

Pre-eclampsia (PE) is a complex multisystem disease of pregnancy that is becoming increasingly recognized as a state of angiogenic imbalance characterized by low concentrations of placental growth factor (PlGF) and elevated soluble fms-like tyrosine kinase (sFlt-1). PlGF is a protein highly expressed by the placenta with vasculogenic and angiogenic properties, which has a central role in spiral artery remodeling and the development of a low-resistance placental capillary network. PlGF concentrations are significantly lower in women with preterm PE, and these reduced levels have been shown to precede the clinical onset of disease. Subsequently, the clinical utility of maternal serum PlGF has been extensively studied in singleton gestations from as early as 11 to 13 weeks' gestation, utilizing a validated multimarker prediction model, which performs superiorly to the National Institute for Health and Care Excellence (NICE) and American College of Obstetricians and Gynecologists (ACOG) guidelines in the detection of preterm PE. There is extensive research highlighting the role of PlGF-based testing utilizing commercially available assays in accelerating the diagnosis of PE in symptomatic women over 20 weeks' gestation and predicting time-to-delivery, allowing individualized risk stratification and appropriate antenatal surveillance to be determined. "Real-world" data has shown that interpretation of PlGF-based test results can aid clinicians in improving maternal outcomes and a growing body of evidence has implied a role for sFlt-1/PlGF in the prognostication of adverse pregnancy and perinatal events. Subsequently, PlGF-based testing is increasingly being implemented into obstetric practice and is advocated by NICE. This literature review aims to provide healthcare professionals with an understanding of the role of angiogenic biomarkers in PE and discuss the evidence for PlGF-based screening and triage. Prospective studies are warranted to explore if its implementation significantly improves perinatal outcomes, explore the value of repeat PlGF testing, and its use in multiple pregnancies.

Comparison of oxidative stress levels during the third Trimester in normal pregnancy and preeclampsia.

The placenta is a complex transiently formed organ which plays a crucial role in the development of the foetus. As the placenta is responsible for maintaining pregnancy placental defects are mainly responsible for pregnancy-related issues. Preeclampsia is a pregnancy-related disorder due to uteroplacental insufficiency resulting from deficient remodelling of spiral arteries causing ischemic reperfusion injury which is finally responsible for the generation of reactive oxygen species and oxidative stress by the placenta. So, this study was planned to determine and compare serum levels of oxidative stress markers (ischemia-modified albumin and malondialdehyde) in preeclampsia and normal pregnancy in the third trimester. Study design: Cross-sectional comparative study Settings Gynae/Obs Department and Pathology Laboratory, Lahore General Hospital, Lahore. Study population: 42 Pregnant females at 34-36 weeks of gestation were selected. Group 1 compromised 21 normal healthy pregnant females and group 2 included 21 preeclamptic patients. Sampling technique: non-probability purposive sampling. Blood samples were taken at 34-36 weeks of gestation. Serum was stored for ischemiamodified albumin and malondialdehyde. Data was analyzed using SPSS version 20. An Independent t-test was used to compare values between the groups during the third trimester. A pvalue of ≤0.05 was considered significant. Comparison of ischemia-modified albumin and malondialdehyde values between group I and group 2 showed a highly significant difference of pvalue of <0.001. Oxidative stress markers were higher in preeclamptic patients as compared to normal pregnant females during the third trimester suggesting the role of the placenta in oxidative stress.

ANP promotes HTR-8/SVneo cell invasion by upregulating protein kinase N 3 via autophagy inhibition.

Preeclampsia is a gestational disease characterized by two major pathological changes-shallow trophoblast invasion and impaired spiral artery remodeling. Atrial natriuretic peptide (ANP) is a kind of peptide hormone that regulates blood pressure, while the lack of active ANP participates in preeclampsia pathogenesis. However, the underlying mechanism of how ANP modulates trophoblasts function remains unclarified. Here, we performed isobaric tags for relative and absolute quantification (iTRAQ) in ANP-treated HTR-8/SVneo cells and identified Protein Kinase 3 (PKN3) as the downstream factor of ANP, which was downregulated in preeclamptic placenta. Chromatin immunoprecipitation analysis and luciferase assays showed that NFYA was one of the transcription factors for the PKN3 promoter, which was also regulated by ANP treatment in HTR-8/SVneo cells. Transmission electron microscopy and Western Blotting in HTR-8/SVneo cells indicated that ANP inhibited autophagy via AMPK-mTORC1 signaling, while excess autophagy was observed in preeclamptic placenta. The increased expression of PKN3 and enhanced cell invasion ability in HTR-8/SVneo cells induced by ANP could be abolished by autophagy activation or transfection with PKN3 shRNA or NFYA shRNA or NPR-A shRNA via regulating the invasion-related genes and the epithelial mesenchymal transition molecules. Our results demonstrated that ANP could enhance trophoblast invasion by upregulating PKN3 via NFYA promotion through autophagy inhibition in an AMPK/mTORC1 signaling-dependent manner.

CCL21/CCR7 Axis Contributes to Trophoblastic Cell Migration and Invasion in Preeclampsia by Affecting the Epithelial Mesenchymal Transition via the ERK1/2 Signaling Pathway.

Preeclampsia (PE) is a pregnancy-related disorder that is a leading cause of maternal death. The failure of spiral artery remodeling due to insufficient trophoblast migration and invasion is critical in the pathogenesis of PE. Recently, the CC motif chemokine ligand 21 (CCL21) has been widely linked to cancer cell invasion and migration. However, their potential mechanisms are still unknown. In this study, we found that CCL21 expression was significantly lower in the PE group than that in the control group. In vitro experiments revealed that recombinant CCL21 could promote trophoblast cell epithelial-to-mesenchymal transitions (EMTs) and improve migration and invasion. Furthermore, an inhibitor of the ERK1/2 signaling pathway inhibited the CCL21-induced EMT process. Finally, a PE mouse model was established using the NOS inhibitor L-NAME, and we obtained similar results, with downregulated CCL21 and EMT biomarkers and upregulated CCR7. Taken together, these findings suggest that the CCL21/CCR7 axis influences EMT by activating the ERK1/2 signaling pathway, thereby affecting trophoblast cell migration and invasion, which may play a crucial role in the pathogenesis of PE.

Uterine NK cells underexpress KIR2DL1/S1 and LILRB1 in reproductive failure.

A significant proportion of recurrent miscarriage, recurrent implantation failure and infertility are unexplained, and these conditions have been proposed to have an etiology of immunological dysfunction at the maternal-fetal interface. Uterine Natural Killer cells (uNK) comprise three subsets and are the most numerous immune cells found in the uterine mucosa at the time of implantation. They are thought to play an important role in successful pregnancy by regulation of extravillous trophoblast (EVT) invasion and spiral artery remodelling. Here, we examine the frequency, phenotype and function of uNK1-3 from the uterine mucosa of 16 women with unexplained reproductive failure compared to 11 controls with no reproductive problems, during the window of implantation. We report that KIR2DL1/S1 and LILRB1 expression is lower in the reproductive failure group for both uNK (total uNK, uNK 2 and 3) and pNK. We also show that degranulation activity is significantly reduced in total uNK, and that TNF-α production is lower in all uNK subsets in the reproductive failure group. Taken together, our findings suggest that reproductive failure is associated with global reduction in expression of uNK receptors important for interaction with HLA-C and HLA-G on EVT during early pregnancy, leading to reduced uNK activation. This is the first study to examine uNK subsets during the window of implantation in women with reproductive failure and will serve as a platform to focus on particular aspects of phenotype and function of uNK subsets in future studies. Further understanding of uNK dysregulation is important to establish potential diagnostic and therapeutic targets in the population of women with unexplained reproductive failure.

Immune response in pregnancy: An evolutionary challenge against external and internal stimuli

Immune response in pregnancy: An evolutionary challenge against external and internal stimuli

Экспрессия ренина и ангиотензинпревращающего фермента 2 в матке и плаценте при иммунозависимых и ассоциированных с преэклампсией спонтанных абортах у мышей

Introduction. Spontaneous abortion and preeclampsia (PE) are the most common pregnancy abnormalities in humans. The renin-angiotensin-aldosterone system (RAAS) and the immune system are among the first to recognize pregnancy and play key roles in its maintenance. RAAS dysfunction is one of the causes of insufficient trophoblast invasion and defect in spiral artery remodeling, which both cause PE. Apart from circulating RAAS components, there are local ones, including uteroplacental ones. The study aimed to analyze the renin and angiotensin-converting enzyme 2 (ACE2) expression in the placenta and uterus in PE-associated spontaneous and immune-dependent abortions in mice. Materials and methods. We reached the physiological pregnancy model by ♀CBA × ♂Balb/c mating (control group); spontaneous PE-associated abortions were ♀CBA × ♂DBA/2. Induced abortions were caused by intraperitoneal β-heptylglycoside muramyldipeptide administration to CBA females fertilized by Balb/c males on gestation days (GDs) 5 and 7. Mice were removed from the experiment on GD 14 after the placenta has completely formed. We performed immunohistochemistry (IHC) of the uterus and placenta using rabbit monoclonal antibodies to renin and ACE2 and evaluated the distribution of the renin- and ACE2-positive cells and the intensity of IHC reaction. Results. Compared to the physiological pregnancy model and immune abortion groups, the spontaneous abortion/PE group was characterized by reduced renin expression in trophoblast giant cells (TGC) and its absence in placental vascular endothelium. We noted increased renin expression in the myometrium and its vascular endothelium in the spontaneous abortion/PE and immune-dependent abortion groups. ACE2 expression in TGC and glycogen cells and placental vascular endothelium was lower in spontaneous/PE and immune-dependent abortions than in the physiological pregnancy group. In contrast, higher ACE2 expression was observed in the myometrium and its vascular endothelium in the abortion groups compared to the controls. Conclusion. Reduced renin expression in TGC and its absence in the placental vascular endothelium of spontaneous abortions/PE group reflects trophoblast invasion disorder characteristic of PE. The detected changes in ACE2 expression in the myometrium in pregnancy failure and PE may represent a systemic compensatory mechanism, which does not exclude the negative effects of renin. Keywords: preeclampsia, pregnancy failure, uterus, placenta, renin-angiotensin-aldosterone system

TIMPs Expression as A Maternal Cell Free Plasma Biomarker of Severe Preeclampsia: A Case-Control Study.

Preeclampsia (PE) is a pregnancy related disorder with prevalence of 6-7%. Insufficient trophoblastic invasion leads to incomplete remodeling of spiral arteries and consequent decrease in feto-placental perfusion. Altered placental expression of tissue inhibitors of matrix metalloproteinase (TIMPs) is considered to be involved in this process while the balance between matrix metalloproteinases (MMPs) and TIMPs contributes to remodeling of the placenta and uterine arteries by degradation and refurbishing of extracellular matrix (ECM). Therefore, TIMPs, fetal expression pattern was evaluated with the aim of its potential to be used as a determinant for the (early) detection of PE. In this case-control study, cell free fetal RNA (cffRNA) released by placenta into the maternal blood was used to determine expression patterns of TIMP1, 2, 3 and 4 in the severe preeclamptic women in comparison with the normal pregnant women. Whole blood from 20 preeclamptic and 20 normal pregnant women in their 28-32 weeks of gestational age was collected. The second control group consisted of 20 normal pregnant women in either 14 or 28 weeks of gestation (each 10). cffRNA was extracted from plasma and real-time polymerase chain reaction (PCR) was done to determine the expression levels of TIMP1, 2, 3 and 4 genes. Statistical analysis of the results showed significant higher expression of TIMP1-4 in the preeclamptic women in comparison with the control group (P=0.029, 0.037, 0.037 and 0.049, respectively). Also, an increased level of TIMPs expression was observed by comparing 14 to 28 weeks of gestational age in the normal pregnant women in the second control group. An increased cffRNA expression level of TIMPs may be correlated with the intensity of placental vascular defect and may be used as a determinant of complicated pregnancies with severe preeclampsia.

Hyperin promotes proliferation, migration, and invasion of HTR-8/SVneo trophoblast cells via activation of JAK1/STAT3 pathway in recurrent spontaneous abortions

The proliferation of extravillous trophoblasts (EVT) and their further migration, invasion, and differentiation into the decidual and myometrial vasculature are vital for spiral artery remodeling. These physiological functions of EVT are also essential steps in the implantation of the human embryo and the formation of the placenta and are closely related to pregnancy maintenance and the occurrence of abortion. Hyperin is a flavonoid with anti-inflammatory, pro-proliferative, and anti-apoptotic properties. Consequently, we investigated the previously unexplored effects of hyperin on the proliferation, migration, and invasion of HTR-8/SVneo cells. Human extravillous trophoblast-derived HTR-8/SVneo cells were incubated with different concentrations of hyperin (0, 5, 10, 25, 50, and 100 μM) to observe the changes in cell proliferation, migration, invasive capacity, and pathway activation. Proliferation, migration, and invasion were promoted by activating the JAK1/STAT3 pathway in HTR-8/SVneo cells treated with hyperin. In addition, brepocitinib (PF-06700841) significantly inhibited the proliferation, migration, and invasion effects of hyperin on HTR-8/SVneo cells. In vivo experiments confirmed that hyperin reduces the embryo loss rate in recurrent spontaneous abortion (RSA) model mice. Furthermore, our study revealed that hyperin promoted the proliferation, migration, and invasion of HTR-8/SVneo cells via activation of the JAK1/STAT3 pathway, further improving pregnancy outcomes in RSA.

Placental basal plate myofibers and risk of hypertensive disorders of pregnancy

Basal plate myofiber (BPMF) refers to the myometrial fibers attachment to the basal plate on placental pathology evaluation. The presence of BPMF may represent occult invasion of placenta or may reflect abnormal placental implantation in a prior pregnancy. It is possible that abnormalities in trophoblast biology associated with BPMF may also alter the physiologic transformation of the spiral arteries in these pregnancies. This study is designed to evaluate the association of BPMF with preeclampsia and gestational hypertension, which are conditions associated with abnormal spiral artery remodeling.

IGF2BP2 enhances LincRNA01116 stability via m6 A: A potential biomarker and therapeutic target for patients with pre-eclampsia.

Pre-eclampsia (PE) is a serious complication in pregnant women characterized by failure of placental remodeling and is one of the primary causes of changes in the placental structure and function. The aberrant expression of long noncoding RNA is associated with the occurrence and progression of PE. This study found that linc01116 expression was significantly downregulated in PE patients and was related to poor uterine spiral artery remodeling. Knockdown of linc01116 remarkably decreased the angiogenesis of trophoblast cells in vitro and in vivo. Mechanistically, IGF2BP2 regulated linc01116 RNA stability via m6 A methylation. Bioinformatics and other experiments further revealed that linc01116 upregulates AAMP expression by adsorbing miR-210-3p in trophoblast cells. In conclusion, this study revealed the critical role of linc01116 in regulating trophoblast angiogenesis. Furthermore, the study provides new clues for detecting placental pathology in PE.

HIF1 inhibitor acriflavine rescues early-onset preeclampsia phenotype in mice lacking placental prolyl hydroxylase domain protein 2.

Preeclampsia is a serious pregnancy disorder that lacks effective treatments other than delivery. Improper sensing of oxygen changes during placentation by prolyl hydroxylases (PHDs), specifically PHD2, causes placental hypoxia-inducible factor-1 (HIF1) buildup and abnormal downstream signaling in early-onset preeclampsia, yet therapeutic targeting of HIF1 has never been attempted. Here we generated a conditional (placenta-specific) knockout of Phd2 in mice (Phd2-/- cKO) to reproduce HIF1 excess and to assess anti-HIF therapy. Conditional deletion of Phd2 in the junctional zone during pregnancy increased placental HIF1 content, resulting in abnormal placentation, impaired remodeling of the uterine spiral arteries, and fetal growth restriction. Pregnant dams developed new-onset hypertension at midgestation (E9.5) in addition to proteinuria and renal and cardiac pathology, hallmarks of severe preeclampsia in humans. Daily injection of acriflavine, a small molecule inhibitor of HIF1, to pregnant Phd2-/- cKO mice from E7.5 (prior to hypertension) or E10.5 (after hypertension had been established) to E14.5 corrected placental dysmorphologies and improved fetal growth. Moreover, it reduced maternal blood pressure and reverted renal and myocardial pathology. Thus, therapeutic targeting of the HIF pathway may improve placental development and function, as well as maternal and fetal health, in preeclampsia.

Morphometry of Placentae of Anaemic and Non-anaemic Preeclamptic Patients

Background&#x0D; The etiology of preeclampsia (PE) still remains elusive. Nevertheless, early onset PE has been hypothesized to develop following defective implantation of the conceptus into the endometrium and subsequent placentation. Defective placentation leads to insufficient remodeling of spiral arteries thus hypoperfusion of the placenta and clinical manifestations. Anaemia is highly prevalent amongst pregnant women. It is postulated that hypoxia is one of the mechanisms by which PE develops. The severity of symptoms seen in patients with coexisting preeclampsia and anaemia has been linked to uteroplacental insufficiency. Few studies however, have defined the placental morphometry when the two conditions occur concurrently.&#x0D; &#x0D; Methods&#x0D; This unmatched case-control study was carried out at the Kenyatta National Hospital where 42 placentae were obtained; 21 from preeclamptic mothers who had anaemia in the first and third trimesters of pregnancy (cases) and 21 from preeclamptic mothers without a history of anaemia in pregnancy (controls). The tissues were obtained and macroscopically and microscopically examined to determine relative differences. Photographs of the placentae were taken using a 12 MP (f/1.8, 26mm wide, 1/2.55", 1.4μm, dual pixel PDAF, OIS) camera. Photomicrographs were taken using a ZeissTM digital photomicroscope at ×400 magnification for stereological analysis. SPSS (Version 25.0) was used to input data where median values, interquartile ranges and frequency tables were obtained. Mann-Whitney U tests were run to compare differences in medians of the clinical, gross and histological features between the 2 groups. A p-value of ≤ _0.05 was considered statistically significant.&#x0D; &#x0D; Results&#x0D; Hemoglobin levels in the anemic group ranged between 7.0-10.5 g/dl in the 1st trimesters and 7.6-10.9g/dl in the 3rd trimester with patients being mild to moderately anemic. Gross placental infarction was observed in 17/21 (81.0%) of the cases and 15/21 (71.4%) of the controls. The gross morphometric parameters that were lower in cases were the placental weight and volume (p-values of &lt;0.001, 0.001 respectively). The histopathological features observed were extensive perivillous and intervillous fibrin deposition and larger volumes of syncytial knots in the case group. The harmonic mean thickness of the interhaemal membrane was higher in the cases when compared to controls (p -value: &lt;0.001). The estimated mean morphometric diffusing capacity was higher in cases when compared to controls (p-value: 0.001).&#x0D; &#x0D; Conclusion&#x0D; The frequency of gross and histopathological lesions seen in the PE placentae was increased when the patients had both preeclampsia and anaemia. Anaemia may thus exacerbate the pathology caused by preeclampsia. This may be the structural basis for the uteroplacental insufficiency observed when the two morbidities co-exist. It may therefore be prudent for clinicians to monitor maternal hemoglobin levels, in order to reduce the severity of preeclampsia when the two conditions co-exist.&#x0D;

Evaluation of Insulin-Like Growth Factor-I (IGF-I) as a Predictor of Preeclampsia

Introduction: Preeclampsia (PE) is a serious pregnancy-induced disease characterized by hypertension, proteinuria and other systemic disorders after 20 weeks of gestation and is a leading cause of maternal and fetal morbidity and mortality. The main pathological characteristics of preeclampsia are poor trophoblast cell invasion and uterine spiral artery remodeling dysfunction caused by placenta ischemia and oxidative stress. Nowadays, preeclampsia is considered to be the results of the interactions of genetic and environmental factors. However, its accurate pathogenesis remains unknown. It was considered IGF-1 might be involved in the pathogenesis of preeclampsia. As is known, the behaviors of cells, the formation of placenta and the growth of fetus are widely regulated by insulin-like growth factor 1 (IGF-1). Several studies have shown that IGF-1 was significantly reduced in preeclampsia. Objectives: To assess the role of Insulin like Growth Factor-I (IGF-I) as a Predictor of Preeclampsia. Materials and Methods: It was a prospective cohort study conducted in General Obstetrics and Gynaecology Unit OPD, Dhaka Medical College Hospital from January, 2020 to December, 2020. Pregnant women between 8 weeks to 15 weeks were enrolled for study after fulfilling selection criteria. Serum concentration of Insulin like growth factor-I (IGF-I) was assessed with cut off value of IGF-I 175.9 ng/ml. The value above 175.9 ng/ml was categorized as normal IGF-I and value below 175.9 ng/ml was categorized as low IGF-I. The patients who had value above 175.9 ng/ml were grouped as A. The value below 175.9 ng/ml was grouped as B. Then they were followed up monthly upto 28 weeks, two weekly upto 36 weeks, weekly upto delivery and puerperium for development of preeclampsia or not. All information was recorded in data collection sheet. Data were analyzed by SPSS-23. Data were compared and correlated among groups and presented by tables and figures. Result: Maternal serum concentration .....

More Tools for Evaluating Decidual Artery Disease.

Introduction: Hypertensive disorders of pregnancy continue to pose the most important risks for adverse maternal and neonatal outcome. Among histological findings, decidual artery disease is one of the most common, one that has both good reproducibility among observers and whose abnormal vascular remodeling is the sole aspect of preeclampsia pathophysiology on which experts agree. Nevertheless, some aspects of arterial remodeling alterations are still under investigation. Methods: We selected 720 routine and consecutive placenta case studies, concordant with the Amsterdam consensus. From these studies, we collected maternal and neonatal clinical data and specific placental findings on spiral artery abnormalities. We took into account all criteria for decidual arteriopathy. Two hundred and fifteen (215) cases out of this population presented hypertensive disorders of pregnancy. Additional to expected arterial findings, we noted frequent persistent parietal trophoblast lining. Results: A large proportion of our population developed hypertensive disorders of pregnancy (30%). Among the histologic findings reported for preeclampsia, we paid particular attention to spiral artery abnormalities, and this interpretive analysis revealed high frequency of arterial remodeling abnormalities. We examined two additional aspects in our routine analysis: first, the novel one of parietal trophoblast persistence, and second, the established problem of associated acute inflammation, as a possible pitfall. Conclusion: In order to better understood, spiral maternal artery remodeling merits further study. The abnormalities in this process provide an objective tool in the study and diagnosis of important pregnancy complications; furthermore, abnormal remodeling is an expression of early pregnancy alteration, and subsequently related to preeclampsia etiology.

Loss of function of membrane estrogen receptor ERα alters expansion of trophoblast cells and impacts mouse fertility

17β-estradiol following binding to estrogen receptor alpha (ERα) exerts a critical role in the control of reproduction, acting through both nuclear and membrane-initiated signaling. To study the physiological role of membrane ERα in the reproductive system, we used the C451A-ERα mouse model with selective loss-of-function of membrane ERα. Despite C451A-ERα mice being described as sterile, daily weighing and ultrasound imaging revealed that homozygous females do get pregnant, allowing to investigate the role of ERα during pregnancy for the first time. Total neonatal deaths of the mice offspring resulted from delayed parturition associated with failure in pre-term progesterone withdrawal. Moreover, pregnant C451A-ERα females exhibit partial intrauterine embryo arrest at about E9.5. The observed embryonic lethality results from altered expansion of Tpbpa-positive spiral artery-associated trophoblast giant cells (SpA-TGCs) into the utero-placental unit, associated with the imbalance expression of angiogenic factors, together controlling the trophoblast-mediated spiral arterial remodeling. Hence, maternal loss of membrane ERα function clearly alters the activity of invasive trophoblast cells during placentogenesis. This novel function of membrane ERα could open new avenues towards a better understanding of human pregnancy-associated pathologies.

Neurological lesions of the mother and the fetus in preeclampsia – an overview of the literature

About 3-5% of pregnancies are complicated by preeclampsia (PE), a multisystem disorder of exact unknown etiology, characterized by new-onset hypertension (&gt;140/90 mmHg), proteinuria, and/or evidence of organ dysfunction. Although it is not yet completely understood what causes PE, maternal and placental factors seem to be involved. Endothelial dysfunction, maternal vascular inflammation, and remodeling of spiral arteries during placentation seem to be the underlying mechanisms of this pregnancy-related disease. Acute PE neurological complications, such as eclamptic seizures, cerebral edema, and intracerebral hemorrhage, are responsible for more than 70% of maternal deaths. Furthermore, long-term complications, such as cognitive dysfunction, the elevated lifetime risk of cerebrovascular disease, and persistent white matter lesions increase the rate of PE-related maternal morbidity and mortality. Hypertensive disorders associated with pregnancy affect not only the mother but also the baby by restricting the supply of nutrients and oxygen to the fetus. This has been associated with impaired cognitive development in children, increased lifetime cerebrovascular, cardiovascular, and metabolic risk, low intelligence quotient (IQ) and mental development indices (MDI), and more depression symptoms later in life. This study aims to review the literature and synthesize available information about preeclampsia and its neurological consequences on both the mother and the fetus.

Ferritin light chain deficiency-induced ferroptosis is involved in preeclampsia pathophysiology by disturbing uterine spiral artery remodelling

The proteomic analysis from samples of patients with preeclampsia (PE) displayed a low level of ferritin light chains (FTL), but we do not know what the significance of reduced FTL in PE pathophysiology is. To address this question, we first demonstrated that FTL was expressed in first- and third-trimester cytotrophoblasts, including extravillous trophoblasts (EVTs), of the human placenta. Furthermore, a pregnant rat model of FTL knockdown was successfully established by intravenously injecting adenoviruses expressing shRNA targeting FTL. In pregnant rats with downregulated FTL, we observed PE-like phenotypes and impaired spiral arterial remodelling, implying a causal relationship between FTL downregulation and PE. Blocking ferroptosis with ferrostatin-1 (Fer-1) significantly rescued the above PE-like phenotypes in pregnant rats with FTL knockdown. Furthermore, using trophoblast cell line and chorionic villous explant culture assays, we showed that FTL downregulation induced cell death, especially ferroptosis, resulting in defective uterine spiral artery remodelling. Eventually, this conclusion from the animal model was verified in PE patients’ placental tissues. Taken together, this study revealed for the first time that FTL reduction during pregnancy triggered ferroptosis and then caused defective uterine spiral artery remodelling, thereby leading to PE.