Spiral Artery Remodeling Research Articles

Tracing the Lipid Fingerprints of Preeclampsia.

Preeclampsia (PE) is the most common pregnancy-related complication responsible for maternal mortality and morbidity. PE pathogenesis is characterized by placental dysfunction, impaired invasion of trophoblast, and defective spiral artery remodelling. Even after many years of research on PE, the etiology and pathophysiology of PE is still elusive. Our earlier studies have shown deregulated maternal and placental fatty acid and lipid metabolism to be associated with the pathogenesis of PE. Currently available lipidomics data have shown that glycerophospholipids, sphingolipid and cholesterol metabolism are mainly altered in preeclampsia. Including these five metabolites (SM C28:1, SM C30:1, LPC C19:0, LPE C20:0, propane-1,3-diol) with currently used protein biomarkers like sFlt-1/PlGF will improve PE prediction. Similarly, CE17:1 and CER(d20:1/24:1) alongwith sFlt-1/PlGF makes a better prediction of PE than sFlt-1/PlGF alone A comprehensive map of lipid profiles in early pregnancy may provide an improved understanding of disease pathogenesis and will be useful predictive biomarkers. In this article, we aimed to summarize the significance of lipid metabolism in the preeclampsia pathogenesis and altered lipidome signatures in preeclampsia. We also discuss the future scope of lipidomics in aiding early prediction of PE and future cardiovascular risk in both mother and child.

Trophoblast cell-derived extracellular vesicles regulate the polarization of decidual macrophages by carrying miR-141-3p in the pathogenesis of preeclampsia

Dysregulation of macrophage polarization can prevent the invasion of trophoblast cells and further limit spiral artery remodeling in preeclampsia (PE). However, its mechanism is obscure. HTR8-/Svneo cells were cultured under normoxic or hypoxic conditions and extracellular vesicles (EVs) in the culture supernatants were extracted. Next, the cells were incubated with those EVs to investigate their effects on trophoblasts. A co-culture system consisting of HTR8-/Svneo cells and macrophages was used to reveal how the trophoblast-derived EVs affected the macrophage subtype. Finally, a PE mouse model and miR-141-3p knockout mice were used to verify the function of miR-141-3p in PE. Hypoxia induced abnormal increases in the levels of miR-141-3p in HTR8-/Svneo cells and EVs. EVs from hypoxia-treated HTR8-/Svneo cells could downregulate PTEN, a potential target of miR-141-3p, and inhibit trophoblast mitophagy and invasion. However, HTR8-/Svneo cells transfected with an miR-141-3p inhibitor could attenuate the influence of EVs. In an HTR8-/Svneo cell plus macrophage co-culture system, hypoxia-pretreated cells promoted the transformation of macrophages into the M1-phenotye, and HTR8-/Svneo invasion was inhibited by the macrophages. MiR-141 from EVs could target and downregulate dual specificity phosphatase 1 (DUSP1) expression in macrophages, induce formation of the M1 macrophage phenotype in THP-1 cells, downregulate DUSP1 expression, and upregulate TAB2/TAK1 signaling. These results were also demonstrated in normal pregnant mice and PE pregnant mice. A hypoxic environment could upregulate miR-141 expression in the EVs of HTR8-/Svneo cells, and THP-1-derived macrophages could uptake EVs releasing miR-141 to downregulate DUSP1 expression and induce the formation of M1 macrophages, which can lead to the development of PE.

The Deubiquitinating Enzyme USP4 Promotes Trophoblast Dysfunction by Stabilizing RYBP.

Previous studies have suggested that impaired spiral artery remodeling, placental dysfunction, and insufficient trophoblast infiltration are the etiology and pathogenesis of Preeclampsia (PE). Ring 1 and YY1 binding protein (RYBP) has been reported to be associated with trophoblast dysfunction. However, the molecular mechanism of RYBP involved in trophoblasts in the pathogenesis of PE is poorly defined. RYBP and Ubiquitin-specific peptidase 4 (USP4) mRNA levels were determined using real-time quantitative polymerase chain reaction (RT-qPCR). RYBP, USP4, p-PI3K, PI3K, p-AKT, and AKT protein levels were measured using western blot assay. Cell viability, proliferation, apoptosis, invasion, and migration were assessed using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, and wound healing assays. After ubibrowser database analysis, the interaction between USP4 and RYBP was verified using Co-immunoprecipitation (CoIP) assay. RYBP and USP4 expression were upregulated in placental tissues from PE patients. By using JEG-3 and HTR-8/SVneo trophoblast cells, RYBP overexpression or USP4 upregulation could hinder cell viability, proliferation, invasion, migration, and promote apoptosis. Mechanistically, USP4 could trigger the deubiquitination of RYBP and prevent its degradation. In addition, USP4 repressed the PI3K/AKT signaling pathway by regulating RYBP. In total, Decreased USP4-mediated ubiquitination results in an adverse impact on trophoblast function by enhancing RYBP expression, providing a novel therapeutic target for PE.

DOCK1 deficiency drives placental trophoblast cell dysfunction by influencing inflammation and oxidative stress, hallmarks of preeclampsia.

Preeclampsia (PE) is a globally prevalent obstetric disorder, pathologically characterized by abnormal placental development. Dysfunctions of angiogenesis, vasculogenesis and spiral artery remodeling are demonstrated to be involved in PE pathogenesis; however, the underlying mechanisms remain largely unknown. Here, we investigated the role of the dedicator of cytokinesis 1 (DOCK1), crucial molecule in various cellular processes, in PE progression using HTR-8 cells derived from first-trimester placental extravillous trophoblasts. Our analysis revealed an aberrant DOCK1 expression in the placental villi of PE patients and its impact on essential cellular functions for vascular network formation. A deficiency of DOCK1 in HTR-8 cells impaired the vascular network formation, exacerbated the expression of anti-angiogenic factor ENG, and reduced VEGF levels. Moreover, DOCK1 knockout amplified apoptosis, as indicated by an altered BCL2: BAX ratio and enhanced levels of cleaved PARP. DOCK1 depletion also boosted NF-κB activation and pro-inflammatory cytokine production (IL-6 and TNF-α). Furthermore, the mice treated with DOCK1 inhibitor, TBOPP, exhibited PE-like symptoms. These findings highlight the multifaceted roles of DOCK1 in the pathophysiology of PE, demonstrating that its deficiency can lead to placental dysfunction by orchestrating inflammatory responses and oxidative stress. These insights emphasize the pathogenic role of DOCK1 in PE development and suggest potential treatment strategies that require further exploration. In the graphical abstract, a split image of placental villi contrasts the effects of normal and reduced DOCK1 expression on preeclampsia. The left side illustrates adequate DOCK1 levels supporting healthy trophoblast function and effective spiral artery remodeling. The right side highlights the consequences of DOCK1 deficiency, leading to trophoblast dysfunction and impaired spiral artery remodeling, accompanied by angiogenic imbalance, increased inflammation, oxidative stress, and apoptosis, contributing to placental dysfunction and the development of preeclampsia.

Maternal blood endometase level as a predictive biomarker for hypertensive disorders during pregnancy: a prospective cohort study

Preeclampsia (PE) occurs due to inadequate spiral artery/trophoblast remodeling in early pregnancy. Endometases are involved in the remodeling of spiral arteries and placental trophoblasts. This study aimed to investigate differences in blood endometase levels between pregnant women with hypertensive disorders (PE and gestational hypertension [GHT]) and healthy pregnant women and to evaluate whether plasma endometase values ​​could play a predictive role in PE or GHT diagnosis. A total of 90 pregnant women (n(PE) = 30, n(GHT) = 30, n(healthy pregnant) = 30) who presented at the hospital between December 2023 and May 2024 and were 26–32 years of age and > 20 weeks pregnant were included in the study. The endometase levels in all pregnant women were determined in maternal blood plasma via enzyme-linked immunosorbent assay. The endometase values were recalculated according to albumin values, and corrected endometase (cEndo) values were determined. No significant differences in blood endometase levels were observed between the groups (p > 0.05). The cEndo value was significantly lower in the PE and GHT groups than in the control group (p < 0.05). There was no statistically significant difference in the cEndo values between the PE and GHT groups (p > 0.05). A statistically significant negative linear relationship was detected between cEndo values and mean systolic blood pressure and mean diastolic blood pressure (p < 0.05). The cEndo values in the PE and GHT groups at early (≤ 32 weeks 3 days) and late pregnancy were compared, and no statistically significant difference was detected (p > 0.05). Maternal blood cEndo values may play a successful role in distinguishing hypertensive diseases of pregnancy (PE + GHT) from healthy pregnant women. cEndo does not play an effective role in the differential diagnosis between pregnant women with PE and those with GHT. Studies with larger patient populations are needed.

The loss of dNK1/2 and EVT1 cells at the maternal-fetal Interface is associated with recurrent miscarriage

Abstract Recurrent miscarriage (RM) is a chronic and heterogeneous pregnancy disorder lacking effective treatment. Alterations at the maternal-fetal interface are commonly observed in RM, with the loss of certain cell subpopulations believed to be a key cause. Through single-cell sequencing of RM patients and healthy donors, we aim to identify aberrancy of cellular features in RM tissues, providing new insights into the research. Natural killer (NK) cells, the most abundant immune cells in the decidua, are traditionally classified into dNK1, dNK2, and dNK3. In this study, we identified a new subset, dNK1/2, absent in RM tissues. This subset was named because it expresses biomarkers of both dNK1 and dNK2. With further analysis, we discovered that dNK1/2 cells play roles in immunoregulation and cytokine secretion. On the villous side of the interface, a notable decrease of extravillous trophoblast (EVT) cells was identified in RM tissues. We clustered EVTs into EVT1 (absent in RM) and EVT2 (retained in RM). Pseudotime analysis revealed distinct differentiation paths, identifying CCNB1, HMGB1, and NPM1 as EVT1 biomarkers. Additionally, we found that EVT1 is involved in the regulation of cell death, while EVT2 exhibited more angiogenic activity. Cell communication analysis revealed that interaction between EVT1 and dNK1/2 mediates chemotaxis and endothelial cell regulation, crucial for spiral artery remodeling. The loss of this interaction may impair decidualization, which is associated with RM. In summary, we propose that the loss of dNK1/2 and EVT1 cells is a significant pathological feature of RM.

Placental lesions in patients with antiphospholipid antibody syndrome: experience of a single tertiary-care Italian reference center

IntroductionAbnormal placentation contributes to obstetric morbidity in antiphospholipid antibodies syndrome (APS). The placenta is the main target of antiphospholipid antibodies (aPL) in obstetric APS and is the site of dysfunctional inflammatory responses and thrombosis. Standard treatment for APS during pregnancy includes low-dose aspirin (LDA) plus low molecular weight heparin (LMWH) and, in refractory cases, hydroxychloroquine (HCQ). Recently, a systematic review of the literature identified five main pathological placental lesions in APS patients: placental infarction, decidual vasculopathy, decidual inflammation, increase of syncytial knots due to syncytiotrophoblast death, and decrease in vasculosyncytial membranes. The aims of this study were to investigate whether placental lesions associate with obstetrical outcomes in a cohort of APS patients.Methods130 pregnant APS patients evaluated between 2009 and 2023 at the High-Risk Obstetrics Outpatient Clinic of San Raffaele Hospital, Milan, were enrolled. Placental samples from 25 spontaneously conceived pregnancies in APS patients were collected from January 2017 to May 2023 and analyzed.ResultsAll (n = 130) patients were on LDA and 110/130 (85%) on both LDA and LMWH. Twenty-six patients (20%) also received HCQ. In these patients, signs of placental inflammation (preterm birth and preterm premature rupture of membranes) were less frequently observed. Of the 25 placental samples analyzed, 19 (76%) patients had primary APS, while 6 patients had APS secondary to SLE. All patients were treated with LDA and LMWH. In patients with concomitant systemic lupus erythematosus (SLE) or in refractory APS, HCQ was added. Histological analysis of placental tissue revealed increased syncytial knots in 17/25 (68%) placentas, decreased vasculosyncytial membranes in 11/25 (44%), infarction in 8/25 (32%), presence of macrophages and decidual inflammation in 2/25 (8%), and atherosis or reduction of spiral artery remodeling in 3/25 (12%). We also observed at least two coexisting placental lesions in 12/25 (48%) placentas. In the placenta of patients treated with HCQ we did not observe any decidual inflammation at histology.ConclusionPlacental anomalies have occurred in patients with APS despite close and optimal obstetric monitoring. It is thus tempting to speculate that HCQ may have beneficial effects on pregnancy by decreasing the risk of deciduitis in patients with APS.

Dysregulated Mitochondrial Calcium Causes Spiral Artery Remodeling Failure in Preeclampsia.

Calcium deficiency in women is strongly linked to an increased risk of developing preeclampsia. Mitochondrial calcium ([Ca2+]m) homeostasis is essential to regulate vascular smooth muscle cell (VSMC) function. However, the role of [Ca2+]m in preeclampsia development remains largely unknown. To investigate this, human spiral arteries obtained from normotensive and preeclamptic women were collected for vascular function, RNA sequencing, and VSMC studies. N(ω)-nitro-L-arginine methyl ester-induced preeclampsia animal experiments were established to investigate the effects of intervening in [Ca2+]m to improve the outcome for preeclamptic mothers or their infants. Our initial findings revealed compromised vessel function in spiral arteries derived from patients with preeclampsia, as evidenced by diminished vasoconstriction and vasodilation responses to angiotensin II and sodium nitroprusside, respectively. Moreover, the spiral artery VSMCs from patients with preeclampsia exhibited phenotypic transformation and proliferation associated with the disrupted regulatory mechanisms of [Ca2+]m uptake. Subsequent in vitro experiments employing gain- and loss-of-function approaches demonstrated that the mitochondrial Na+/Ca2+ exchanger played a role in promoting phenotypic switching and impaired mitochondrial functions in VSMCs. Furthermore, mtNCLX (mitochondrial Na+/Ca2+ exchanger) inhibitor CGP37157 significantly improved VSMC phenotypic changes and restored mitochondrial function in both patients with preeclampsia-derived VSMCs and the preeclampsia rat model. This study provides comprehensive evidence supporting the disrupted regulatory mechanisms of [Ca2+]m uptake in VSMCs of spiral arteries of patients with preeclampsia and further elucidates its correlation with VSMC phenotypic switching and defective spiral artery remodeling. The findings suggest that targeting mtNCLX holds promise as a novel therapeutic approach for managing preeclampsia.

A Hypoxia-Decidual Macrophage Regulatory Axis in Normal Pregnancy and Spontaneous Miscarriage.

The significance of hypoxia at the maternal-fetal interface is proven to be self-explanatory in the context of pregnancy. During the first trimester, low oxygen conditions play a crucial role in processes such as angiogenesis, trophoblast invasion and differentiation, and immune regulation. Recently, there has been increasing research on decidual macrophages, which contribute to the maintenance of immune tolerance, placental and fetal vascular development, and spiral artery remodeling, to investigate the effects of hypoxia on their biological behaviors. On these grounds, this review describes the dynamic changes in oxygen levels at the maternal-fetal interface throughout gestation, summarizing current knowledge on how the hypoxic environment sustains a successful pregnancy by regulating retention, differentiation and efferocytosis of decidual macrophages. Additionally, we explore the relationship between spontaneous miscarriages and an abnormal hypoxia-macrophage axis, shedding light on the underlying mechanisms. However, further studies are essential to elucidate these pathways in greater detail and to develop targeted interventions that could improve pregnancy outcomes.

B-flow/spatiotemporal image correlation M-mode ultrasound provides novel method to quantify spiral artery remodeling during normal human pregnancy.

During human pregnancy, placental extravillous trophoblasts replace vascular smooth muscle and elastic tissue within the walls of the uterine spiral arteries, thereby remodeling them into distensible low-resistance vessels to promote placental perfusion. The present study determined whether B-flow/spatiotemporal image correlation (STIC) M-mode ultrasonography provides an in-vivo imaging method able to digitally quantify spiral artery luminal distensibility as a physiological index of spiral artery remodeling during the advancing stages of normal human pregnancy. A prospective, longitudinal, observational study was conducted to quantify spiral artery distensibility (i.e. vessel luminal diameter at systole minus diameter at diastole) by B-flow/STIC M-mode ultrasonography during the first, second and third trimesters in 290 women exhibiting a normal pregnancy. Maternal serum levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1), growth factors that modulate important events in spiral artery remodeling, were quantified in a subset of the women in the first, second and third trimesters of pregnancy. Median (interquartile range (IQR)) spiral artery distensibility increased progressively between the first (0.17 (0.14-0.21) cm), second (0.23 (0.18-0.28) cm) and third (0.26 (0.21-0.35) cm) trimesters of pregnancy (P < 0.0001 for all). Median (IQR) spiral artery volume flow increased progressively between the first (2.49 (1.38-4.99) mL/cardiac cycle), second (3.86 (2.06-6.91) mL/cardiac cycle) and third (7.79 (3.83-14.98) mL/cardiac cycle) trimesters (P < 0.001 for all). In accordance with the elevation in spiral artery distensibility, the median (IQR) ratio of serum PlGF/sFlt-1 × 103 levels increased between the first (7.2 (4.5-10.0)), second (22.7 (18.6-42.2)) and third (56.2 (41.9-92.5)) trimesters (P < 0.001 for all). The present study shows that B-flow/STIC M-mode ultrasonography provides an in-vivo imaging technology to quantify digitally the structural and physiological expansion of the walls of the spiral arteries during the cardiac cycle as a consequence of their transformation into compliant vessels during advancing stages of normal human pregnancy. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Metabolic theory of preeclampsia: implications for maternal cardiovascular health.

Preeclampsia (PE) is a multisystemic disorder of pregnancy that not only causes perinatal mortality and morbidity but also has a long-term toll on the maternal and fetal cardiovascular system. Women diagnosed with PE are at greater risk for the subsequent development of hypertension, ischemic heart disease, cardiomyopathy, cerebral edema, seizures, and end-stage renal disease. Although PE is considered heterogeneous, inefficient extravillous trophoblast (EVT) migration leading to deficient spiral artery remodeling and increased uteroplacental vascular resistance is the likely initiation of the disease. The principal pathophysiology is placental hypoxia, causing subsequent oxidative stress, leading to mitochondrial dysfunction, mitophagy, and immunological imbalance. The damage imposed on the placenta in turn results in the "stress response" categorized by the dysfunctional release of vasoactive components including oxidative stressors, proinflammatory factors, and cytokines into the maternal circulation. These bioactive factors have deleterious effects on systemic endothelial cells and coagulation leading to generalized vascular dysfunction and hypercoagulability. A better understanding of these metabolic factors may lead to novel therapeutic approaches to prevent and treat this multisystemic disorder. In this review, we connect the hypoxic-oxidative stress and inflammation involved in the pathophysiology of PE to the resulting persistent cardiovascular complications in patients with preeclampsia.

High-fat, high-sucrose diet-induced obesity disrupts mid-gestational decidual inflammatory and vascular homeostasis without impairing spiral artery remodelling.

High-fat, high-sucrose diet-induced obesity disrupts mid-gestational decidual inflammatory and vascular homeostasis without impairing spiral artery remodelling.

Trophoblast Stem Cells Induce Spiral Artery Remodeling in an Ex Vivo Model of the Human Placental Decidual Interface

Trophoblast Stem Cells Induce Spiral Artery Remodeling in an Ex Vivo Model of the Human Placental Decidual Interface

Prevalence of placental bed spiral artery pathology in preeclampsia and fetal growth restriction: A prospective cohort study

BackgroundPreeclampsia and fetal growth restriction (PE/FGR) are pregnancy complications known to be associated with poor utero-placental function due to abnormal “physiological” remodeling of spiral arteries and unfavorable maternal cardiovascular health. However, the prevalence and degree of impaired spiral artery remodeling has not been clearly established. MethodProspective, multi-center observational cohort study to assess the prevalence of lesions associated with abnormal development of spiral arteries in placental bed biopsies systematically obtained from 121 women undergoing Caesarian section for PE/FGR compared with a reference group of 149 healthy controls. ResultsPE/FGR was associated with a high prevalence of impaired spiral artery remodeling compared with controls (63.6 vs 10.1 %, p < 0.001), and a higher prevalence of non-remodeled spiral arteries without the presence of intramural trophoblast (45.5 vs 6.7 %, p < 0.001), despite abundant interstitial trophoblast invasion in surrounding decidua and myometrium. Normal remodeling was associated with circumferential presence of intramural trophoblast and hardly any trophoblast in surrounding tissue. Acute atherosis (28.9 vs 3.4 %, p < 0.001) and thrombosis (16.5 vs 5.4 %, p = 0.003) lesions were significantly more prevalent in PE/FGR. Impaired remodeling, acute atherosis and thrombosis lesions were equally present in both decidual and myometrial segments of the spiral arteries in both groups. Impaired remodeling was most prominent in the groups with FGR (with or without PE) and thrombosis was most often seen in the group with PE and FGR. ConclusionPE/FGR is associated with a high prevalence of impaired physiological remodeling and vascular lesions of the uterine spiral arteries in the placental bed.

Impact of the Immunomodulatory Factor Soluble B7-H4 in the Progress of Preeclampsia by Inhibiting Essential Functions of Extravillous Trophoblast Cells.

A key aspect of preeclampsia pathophysiology is the reduced invasiveness of trophoblasts and the impairment of spiral artery remodelling. Understanding the causes of altered trophoblast function is critical to understand the development of preeclampsia. B7-H4, a checkpoint molecule, controls a wide range of processes, including T-cell activation, cytokine release, and tumour progression. Our previous findings indicated that B7-H4 levels are elevated in both maternal blood and placental villous tissue during the early stages of preeclampsia. Here, we investigated the function of B7-H4 in trophoblast physiology. Recombinant B7-H4 protein was used to treat human SGHPL-5 extravillous trophoblast cells. Biological functions were investigated using MTT, wound healing, and transwell assays. Signalling pathways were analysed by immunoblotting and immunofluorescence. The functionality of B7-H4 was further confirmed by immunoblotting and immunohistochemical analysis in placental tissues from control and preeclamptic patients following therapeutic plasma exchange (TPE) or standard of care treatment. This study showed that B7-H4 inhibited the proliferation, migration, and invasion capacities of SGHPL-5 extravillous cells while promoting apoptosis by downregulating the PI3K/Akt/STAT3 signalling pathway. These results were consistently confirmed in placental tissues from preterm controls compared to early-onset preeclamptic placental tissues from patients treated with standard of care or TPE treatment. B7-H4 may play a role in the development of preeclampsia by inhibiting essential functions of extravillous trophoblast cells during placental development. One possible mechanism by which TPE improves pregnancy outcomes in preeclampsia is through the elimination of B7-H4 amongst other factors.

Targeting Decidual CD16+ Immune Cells with Exosome-Based Glucocorticoid Nanoparticles for Miscarriage.

Immune dysfunction in early pregnancy including overactivation of cytotoxic CD16+ NK cells and proinflammatory M1 macrophages at the maternal-fetal interface interferes with trophoblast invasion, spiral artery remodeling, and decidualization, potentially leading to miscarriage. Immunosuppressants like glucocorticoids (GCs) are used to regulate the immune microenvironment in clinical treatment, but the lack of safe and efficient tissue-specific drug delivery systems, especially immune cell-specific vectors, limits their widespread clinical application. Here, a previously uncharacterized delivery system is reported, termed GC-Exo-CD16Ab, in which GCs are loaded into purified exosomes derived from human umbilical cord mesenchymal stem cells, and subsequently decorated with antibody CD16Ab. GC-Exo-CD16Ab is biocompatible and has remarkable delivery efficiency toward CD16+ decidual natural killer (NK) cells and CD16+ macrophages in mice. This innovative approach effectively suppresses the cytotoxicity of decidual NK cells, inhibits M1 macrophage polarization, and regulates the decidual microenvironment, thereby enhancing placental and fetal morphology, and ultimately mitigating miscarriage risk in the abortion-prone mice. The developed GC-Exo-CD16Ab provides a feasible platform for precise and tissue-specific therapeutic strategies for miscarriage and pregnancy-related diseases.

LINC01410 accelerates the invasion of trophoblast cells by modulating METTL3/Fas.

Insufficient trophoblast invasion, culminating in suboptimal uterine spiral artery remodeling, is pinpointed as a pivotal contributor to preeclampsia (PE) development. LINC01410 has been documented to be increased in various neoplasms, and is significantly associated with the invasive capabilities of tumor cells. Nonetheless, its function and the mechanisms in the pathogenesis of PE require further investigation. LINC01410 and methyltransferase-like 3 (METTL3) were ectopically expressed in HTR-8/Svneo cells via lentiviral transduction. Subsequently, the cells' invasive capabilities and apoptosis rates were evaluated employing Transwell assays and flow cytometry, respectively. The interplay between LINC01410 and METTL3, alongside the m6A methylation of FAS, was probed through RNA immunoprecipitation (RIP). Additionally, the association between FAS and METTL3 was elucidated via Coimmunoprecipitation (Co-IP) assays. The protein level of NF-κB, BAX, and BCL-2 in LINC01410-overexpressing cells was detected by Western blot. Our findings revealed that LINC01410 elevation increased the invasive ability of HTR-8/Svneo cells, directly impacting METTL3 then leading to its reduced expression. Conversely, heightened METTL3 expression mitigated invasiveness while enhancing apoptosis in these cells. Moreover, METTL3's interaction with FAS led to increased FAS expression, subject to m6A methylation. A surge in LINC01410 markedly decreased both mRNA and protein levels of FAS. Furthermore, LINC01410 overexpression significantly reduced NF-κB and BAX protein levels while augmenting BCL-2. Upregulation of LINC01410 expression promotes trophoblast cell invasion by inhibiting FAS levels through modified m6A alteration and suppressing the NF-κB pathway. These findings underscore the pivotal role of LINC01410 in regulating trophoblast cell invasion and propose it as a promising therapeutic strategy for preventing or alleviating PE. This offers valuable insights for the clinical treatment of PE, for which definitive targeted therapy methods are currently lacking.

Human amniotic epithelial cells improve uterine spiral artery remodeling to ameliorate preeclampsia in a rat model†.

Preeclampsia (PE) is a multisystem pregnancy disorder characterized by impaired remodeling of placental spiral arteries, which leads to the release of pro-inflammatory cytokines and anti-angiogenic agents. However, treatment options for PE are limited, with termination of pregnancy being the only curative option. In this work, we investigated the effects of human amniotic epithelial cells (hAECs) in PE rat model. The rats were induced with lipopolysaccharide (LPS) on gestational day 14.5 followed by injection of hAECs and human umbilical cord mesenchymal stem cells 24h later. The hAECs treatment resulted in a reduction in blood pressure and proteinuria in the PE rat model. Furthermore, hAECs treatment decreased levels of pro-inflammatory cytokines, reduced inflammatory cells aggregation, and alleviated the damage to placental spiral arteries by downregulating the expression of anti-angiogenic factor and upregulating proangiogenic factor. In vitro experiments confirmed that hAECs treatment restored the proliferation, migration, and angiogenesis of LPS-damaged human umbilical vein endothelial cells. Additionally, hAECs treatment had positive effects on fetal weight and neurological development in the PE group, with no negative effects on the physical development or fertility of offspring rats. These results suggested that hAECs transplantation may be a novel adjuvant therapeutic strategy for PE by reducing the inflammatory and enhancing placental spiral artery angiogenesis.

Increased EHD1 in trophoblasts causes RSM by activating TGFβ signaling.

Recurrent spontaneous miscarriage (RSM) is one of the complications during pregnancy. However, the pathogenesis of RSM is far from fully elucidated. Since the endocytic pathway is crucial for cellular homeostasis, our study aimed to explore the roles of endocytic recycling, especially EH domain containing 1 (EHD1), a member of the endocytic recycling compartment, in RSM. We first investigated the expression of the endocytic pathway member EHD1 in villi from the normal and RSM groups. Then, we performed RNA sequencing and experiments in villi, HTR8 cells and BeWo cells to determine the mechanisms by which EHD1 induced RSM. Finally, placenta-specific EHD1-overexpressing mice were generated to investigate the RSM phenotype in vivo. EHD1 was expressed in extravillous trophoblasts (EVTs) and syncytiotrophoblast (STB) in the villi. Compared with the control group, RSM patients expressed higher EHD1. A high level of EHD1 decreased proliferation, promoted apoptosis, and reduced the migration and invasion of HTR8 cells by activating the TGFBR1-SMAD2/3 signaling pathway. The TGFBR1 antagonist LY3200882 partially reversed the EHD1 overexpression-induced changes in the cell phenotype. Besides, a high level of EHD1 also induced abnormal syncytialization, which disturbed maternal-fetal material exchanges. In a mouse model, placenta-specific overexpression of EHD1 led to the failure of spiral artery remodeling, excessive syncytialization and miscarriage. Increased expression of EHD1 impaired the invasion of EVTs mediated by the TGFBR1-SMAD2/3 signaling pathway and induced abnormal syncytialization of STB, which is at least partially responsible for RSM.

RNA-binding protein SORBS2 increases human trophoblast cell migration via stabilizing HK2 mRNA in preeclampsia.

SORBS2, an RNA-binding protein, is identified as a regulator of aerobic glycolysis, which is essential for trophoblast migration and placental development. Reduced SORBS2 expression in preeclampsia may impair trophoblast migration by affecting mRNA stability and glycolysis, suggesting its role in the disease's pathogenesis. Insufficient trophoblast migration and impaired uterine spiral artery remodeling are implicated in the pathogenesis of preeclampsia, contributing to inadequate placentation. However, the molecular mechanism underlying this process remains unclear. Aerobic glycolysis, which produces substantial lactate, is crucial for establishing a favorable microenvironment for early uterine preparation and supporting embryo implantation and trophoblast migration. In the present study, we have demonstrated that SORBS2, an RNA-binding protein, regulated aerobic glycolysis and significantly improved trophoblast migration in vitro. Our results showed that SORBS2 expression was significantly reduced in human PE placentas and trophoblasts during hypoxia. Overexpression of SORBS2 enhanced cell proliferation and migration, whereas knockdown of SORBS2 decreased these functions in HTR-8/SVneo cells. Mechanistic studies have demonstrated that SORBS2 directly interacts with the 3' untranslated regions (UTRs) of key glycolysis-related genes, specifically HK2. This interaction results in enhanced stability of HK2 and activation of glycolysis. Moreover, silencing HK2 abrogated the enhancement of proliferation and migration of HTR-8/SVneo cells induced by SORBS2. In conclusion, our findings suggest that the downregulation of SORBS2 may contribute to the pathogenesis of preeclampsia by regulating mRNA stability and inhibiting trophoblast migration during placentation.