Spiral Artery Remodeling Research Articles

The long noncoding RNA TARID regulates the CXCL3/ERK/MAPK pathway in trophoblasts and is associated with preeclampsia

BackgroundThe widely accepted explanation of preeclampsia (PE) pathogenesis is insufficient trophoblast invasion and impaired uterine spiral artery remodeling. However, the underlying molecular mechanism remains unclear.MethodsWe performed transcriptome sequencing on placentas of normal and PE patients and identified 976 differentially expressed long noncoding RNAs (lncRNAs). TCF21 antisense RNA inducing demethylation (TARID) was one of the most significantly differentially expressed lncRNAs and was negatively correlated with the systolic and diastolic blood pressure in PE patients. Furthermore, we verified the effect of TARID on the biological behavior of trophoblasts and performed UID mRNA-seq to identify the effectors downstream of TARID. Then, co-transfection experiments were used to better illustrate the interaction between TARID and its downstream effector.ResultsWe concluded that the downregulation of TARID expression may inhibit trophoblast infiltration and spiral artery remodeling through inhibition of cell migration, invasion, and tube formation mediated through the CXCL3/ERK/MAPK pathway.ConclusionsOverall, these findings suggested that TARID may be a therapeutic target for PE through the CXCL3/ERK/MAPK pathway.

Utilizing the Knowledge of Role of Matrix Matrixmetalloproteinases Along with Tissue Inhibitors of Matrix Metalloproteinasesin Various Gynaecological Disorders with Great Emphasis on Preeclampsia, PCOs Along with Gynaecological Malignancies-A Systematic Review

Our insight has escalated over the past decade regarding the understanding of Molecular mechanisms underlying the generation of preeclampsia, with us reviewing the role of epigenetics in the development of preeclampsia along with intra uterine growth restriction (IUGR) generation. Matrix Metalloproteinases (MM’s) MMP’s represent calcium-based zinc-endopeptidases that belong to the metzincin superfamily possessing a lot of functions like a physiological part in tissue morphogenesis, cell migration along with angiogenesis as well as in pregnancy in invasion along with migration of trophoblast besides spiral artery remodeling. Matrix Metalloproteinases (MMP), cytokines, growth factors have a role in physiological events like embryo implantation, trophoblast invasion as well as migration along with decidualization with studies documented that blastocysts are direct generators of MMP2. Thus here we decided to conduct a systematic review on the role of Matrix Metalloproteinases (MMP’s) along with their inhibitors,namely the, Tissue inhibitors of Matrix Metalloproteinases (TIMPs) in gynaecological disorders specifically in generation of preeclampsia along with IUGR; in women with Polycystic Ovarian Syndrome(PCOS); besides in spontaneous abortion along with generation of various cancers of the whole body but main emphasis on gynaecological cancers .Hence utilizing the search engine Thus we utilized Pubmed, MEDLINE, Google Scholar, Scopus, Embase, Web of Sciences, Cochrane library search engines where we utilized the MeSH terms like MMP’s in pregnancy physiological roles; pathological in preeclampsia, IUGR; miRs in these disorders; spontaneous abortion; gynaecological disorders like PCOS; gynaecological cancer along with association of certain MIR’s abnormal in IUGR that were linked to certain gliomas along with MMP’S and IUGR and further utilization of MMP inhibitors clinically, besides that since no efficacious therapy available other therapies like role of extracellular vesicles (ECV’s) that target combined miR’S that are altered and associated with MMP’s in various pathologies and effectively we can treat those disorders from 1970 till January 2021 till date. We found a total of 500 articles out of which we selected 145 articles for this review following evaluation of cross references. No meta-analysis was done. Here we provide an insight on how this knowledge on molecular mechanisms interactions of MMP’s, TIMP’s micro RNA’S might get utilized in generating therapies to prevent or treat preeclampsia, IUGR, various gynaecological malignancies developing extracellular vesicles carrying miR;s targeting specific MMP’s in particular disease or malignancy.

Natural killer cell-mediated immunopathology in recurrent pregnancy losses

Natural killer (NK) cells have a dual role in human reproduction for maternal-fetal tolerance and protection from infection. During the ovarian cycle and pregnancy, peripheral NK (pNK) and uterine NK (uNK) cells dynamically change their proportions and cytotoxicities to prepare and accommodate invading trophoblast and maintain pregnancy. However, dysregulated pNK and uNK cell proportions and cytotoxic activities have been associated with aberrant spiral artery remodeling and trophoblast invasion, leading to implantation failures and recurrent pregnancy losses (RPLs). This review will focus on the role of NK cells in RPLs reviewing the ontogeny of NK cells, changes in pNK and uNK cell levels, and activities during the ovarian cycle, normal pregnancy, and RPL. In addition, the immunopathological role of NK cells in endometrial/decidual vascular development and killer immunoglobin-like receptor (KIR) and human leukocyte antigen (HLA)-C interactions are discussed.

The Effect of Pravastatin on Hypoxia Inducible Factor-1-Alpha (HIF-1-A) Expression on the Placenta of Preeclampsia Wistar Rats

Background: Preeclampsia (PE) is hypertension in pregnancy that currently occurs starting from the time of placentation and is 1 of the five leading causes of maternal death. The main cause of preeclampsia is the placenta, which is hypoxic, and the spiral artery remodeling fails. Hypoxia-inducible factor-1-alpha (HIF-1-A), a marker in the nucleus, is overexpressed during tissue hypoxia. Pravastatin has a pleiotropic effect as the synthesis of nitric oxide (NO), a strong vasodilator to correct hypoxia. This study aims to explore the potential of pravastatin against functional abnormalities or placental hypoxia through in vivo HIF-1-A expression.
 Methods: This study is an experimental study using female Wistar rats (Rattus norvegicus) induced by preeclampsia. Assessment of HIF-1-A expression was carried out by immunohistochemistry. Data analysis was performed using SPSS, and then univariate and bivariate tests were performed.
 Results: Administration of pravastatin at a dose of 10 mg/kg BW showed the most optimal potential in reducing the expression of HIF-1-A protein, indicating tissue hypoxia. Pravastatin doses of 2.5 mg/kg BW and 5 mg/kg BW also could reduce HIF-1-A protein expression better than the K+ group who were not given pravastatin.
 Conclusion: Pravastatin can reduce the expression of HIF-1-A protein in pre-eclamptic rats, which indicates the potential of pravastatin to reduce the incidence of preeclampsia.

PVT1/miR-145-5p/HK2 modulates vascular smooth muscle cells phenotype switch via glycolysis: The new perspective on the spiral artery remodeling

IntroductionVascular smooth muscle cells (VSMC) switched from a contractile phenotype to a synthetic phenotype during the decidual spiral artery (SPAs) remodeling process. The lncRNA plasmacytoma variant translocation 1 (PVT1) and glucose metabolism have been found to regulate the VSMC phenotype switch. This study aimed to analyze the dynamic expression of PVT1 and glycolytic key enzymes hexokinase2 (HK2) at different remodeling stages in early human pregnancy and elucidate the underlying mechanism of the PVT1/miR-145-5p/HK2 axis involved in the spiral artery remodeling. MethodsqRT-PCR, Western blot (WB) analysis, Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were used to detect the expression and localization of PVT1 and HK2 in decidual tissue. HA-VSMCs were transfected with specific siRNA, shRNA and plasmids to regulate corresponding genes. Extracellular lactate, cellular ATP, ROS, and intracellular NADPH levels were measured using the corresponding assay kits. Migration was measured by wound-healing and Transwell assays. Contractile phenotypic markers α-SMA, MYH11 with calponin and synthetic phenotypic markers OPN and vimentin were detected by WB. The PDC model was used to detect the degree of spiral arterial remodeling. ResultsPVT1 and HK2 were upregulated with gestational age (GA) increasing in decidual tissue during the early pregnancy. HK2 regulated the glycolytic activity and VSMC phenotype switch in vitro. PVT1 regulated the glycolytic activity and VSMC phenotype switch through HK2. PVT1 played a ceRNA role in regulating HK2 expression by sponging miR-145-5p. PVT1 and HK2 influenced spiral artery remodeling in the PDC model. DiscussionPVT1 and HK2 were upregulated, and miR-145-5p was downregulated in decidua with the GA increasing. Meanwhile, the PVT1/miR-145-5p/HK2 axis may be involved in regulating the phenotypic switch and migratory capacity of VSMCs by affecting glycolysis in decidual SPAs remodeling.

Impaired renal reserve contributes to preeclampsia via the kynurenine and soluble fms-like tyrosine kinase 1 pathway.

To understand how kidney donation leads to an increased risk of preeclampsia, we studied pregnant outbred mice with prior uninephrectomy and compared them with sham-operated littermates carrying both kidneys. During pregnancy, uninephrectomized (UNx) mice failed to achieve a physiological increase in the glomerular filtration rate and during late gestation developed hypertension, albuminuria, glomerular endothelial damage, and excess placental production of soluble fms–like tyrosine kinase 1 (sFLT1), an antiangiogenic protein implicated in the pathogenesis of preeclampsia. Maternal hypertension in UNx mice was associated with low plasma volumes, an increased rate of fetal resorption, impaired spiral artery remodeling, and placental ischemia. To evaluate potential mechanisms, we studied plasma metabolite changes using mass spectrometry and noted that l-kynurenine, a metabolite of l-tryptophan, was upregulated approximately 3-fold during pregnancy when compared with prepregnant concentrations in the same animals, consistent with prior reports suggesting a protective role for l-kynurenine in placental health. However, UNx mice failed to show upregulation of l-kynurenine during pregnancy; furthermore, when UNx mice were fed l-kynurenine in drinking water throughout pregnancy, their preeclampsia-like state was rescued, including a reversal of placental ischemia and normalization of sFLT1 levels. In aggregate, we provide a mechanistic basis for how impaired renal reserve and the resulting failure to upregulate l-kynurenine during pregnancy can lead to impaired placentation, placental hypoperfusion, an antiangiogenic state, and subsequent preeclampsia.

BCAM Deficiency May Contribute to Preeclampsia by Suppressing the PIK3R6/p-STAT3 Signaling.

Preeclampsia is a pregnancy syndrome that may utilize multiple pathogenic mechanisms. Insufficient trophoblast invasion and impaired uterine spiral artery remodeling are believed to be the pathological basis; yet the underlying mechanisms remain largely unclear. The placental BCAM (basal cell adhesion molecule) expression and important clinical indicators were detected and correlation analysis was performed. MiRNAs directly targeting BCAM were predicted and further verified by dual-luciferase reporter gene, and the downstream molecular mechanisms of BCAM were investigated in both HTR-8/SVneo and JAR cells. In addition, pregnant/nonpregnant rats were treated with adenoviruses containing BCAM shRNA genes (Ad-shBCAM) on gestational 9.5 days to detect the preeclamptic features. The BCAM is highly expressed on the trophoblast membrane and decreased in the preeclamptic placentae. In HTR-8/SVneo and JAR cells, BCAM knockdown inhibited trophoblast proliferation, migration, and invasion, and suppressed phosphorylation on Y705 of STAT3 dependent on the downregulation of PIK3R6. Moreover, miR-199a-5p mediated the degradation of BCAM and also inhibited trophoblast proliferation, migration, and invasion. In vivo, BCAM deficiency induced a preeclampsia-like phenotype included elevated systolic blood pressure, proteinuria, impaired morphology and function of multiple organs (placenta, liver, and kidney), and fetal growth restriction. The expression of placenta BCAM/PIK3R6/p-STAT3 signaling was also downregulated in this preeclampsia rat model. MiR-199a-5p mediated-BCAM deficiency contributes to the suppression of trophoblast proliferation, migration, and invasion by inhibiting PIK3R6/p-STAT3 signaling, which may lead to poor placentation and result in preeclampsia-like phenotypes. Our study provides a new academic perspective on the pathogenesis of preeclampsia.

Vascular adhesion protein-1 (VAP-1) in vascular inflammatory diseases.

Vascular adhesion protein-1 (VAP-1) also known as amino oxidase copper containing 3 (AOC3) is a pro-inflammatory and versatile molecule with adhesive and enzymatic properties. VAP-1 is a primary amine oxidase belonging to the semicarbazide-sensitive amine oxidase (SSAO) family, which catalyzes the oxidation of primary amines leading to the production of ammonium, formaldehyde, methylglyoxal, and hydrogen peroxide. VAP-1 is mainly expressed by endothelial cells, smooth muscle cells, adipocytes and pericytes. It is involved in a repertoire of biological functions, e.g., immune cell extravasation, angiogenesis, and vascularization. Research into VAP-1 has intensified within the last decade on its role as a novel clinical biomarker and as a potential therapeutic target of vascular inflammatory disorders such as atherosclerosis, stroke, diabetes, neurovascular disorders (e.g., Alzheimer's Disease), hepatic disease (e.g., non-alcoholic steatohepatitis), and skin conditions (e.g., psoriasis). This is the most up-to-date and comprehensive review on VAP-1 focusing on the translational aspects of VAP-1. Compared to recent reviews, our review provides novel insights on VAP-1 and heart failure, stroke and frailty, diabetes, endometriosis, osteoarthritis, COVID-19, conjunctivitis associated systemic lupus erythematosus, hematopoietic stem cells, gliomas, treatment of colorectal cancer with a novel VAP-1 inhibitor (U-V269), promoting recovery of motor functions and habit learning with a novel VAP-1 inhibitor (PXS-4681A), and 68Ga-DOTA-Siglec-9, a labelled peptide of Siglec-9 (a VAP-1 ligand), which appears to be a safe PET tracer for inflammation in rheumatoid arthritis. Finally, we present the emerging role of VAP-1 in pregnancy as a gatekeeper of immune cells, which are critical for spiral arterial remodeling, the deficiency of which could lead to vascular disorders of pregnancy such as preeclampsia. Future research should prioritize clinical trials on VAP-1 small-molecule inhibitors and monoclonal antibodies, thus, maximizing the potential of VAP-1 targeted therapy as well as research into sVAP-1 as a clinical biomarker of diseases and its prognosis.

Role of microRNAs in trophoblast invasion and spiral artery remodeling: Implications for preeclampsia.

It is now well-established that microRNAs (miRNAs) are important regulators of gene expression. The role of miRNAs in placental development and trophoblast function is constantly expanding. Trophoblast invasion and their ability to remodel uterine spiral arteries are essential for proper placental development and successful pregnancy outcome. Many miRNAs are reported to be dysregulated in pregnancy complications, especially preeclampsia and they exert various regulatory effects on trophoblasts. In this review, we provide a brief overview of miRNA biogenesis and their mechanism of action, as well as of trophoblasts differentiation, invasion and spiral artery remodeling. We then discuss the role of miRNAs in trophoblasts invasion and spiral artery remodeling, focusing on miRNAs that have been thoroughly investigated, especially using multiple model systems. We also discuss the potential role of miRNAs in the pathogenesis of preeclampsia.

Altered extracellular mRNA communication in postpartum depression is associated with decreased autophagy.

We investigated whether extracellular RNA communication, which is a recently discovered mode of intercellular communication that is involved in a variety of important biological processes including pregnancy, is associated with postpartum depression (PPD). Extracellular RNA communication is increased during pregnancy and is involved in embryo implantation, uterine spiral artery remodeling, parturition, preterm birth, immunity, and the inflammatory response. Since immune anomalies are associated with PPD, we characterized the mRNA content of extracellular vesicles (EV) in a cohort of prospectively collected blood plasma samples at six time-points throughout pregnancy and the postpartum (2nd trimester, 3rd trimester, 2 weeks postpartum, 6 weeks postpartum, 3 months postpartum, and 6 months postpartum) in an academic medical setting from women who went on to develop PPD (N = 7, defined as euthymic in pregnancy with postpartum-onset depressive symptoms assessed by Edinburgh Postnatal Depression Scale ≥13 at any postpartum time point) and matched unaffected controls (N = 7, defined as euthymic throughout pregnancy and postpartum). Blood samples were available for all participants at the T2 and W6 timepoints, with fewer samples available at other time points. This analysis revealed that EV mRNA levels during pregnancy and the postpartum period were extensively altered in women who went on to develop PPD. Gene set enrichment analysis revealed that mRNAs associated with autophagy were decreased in PPD cases. In contrast, EV mRNAs from ribosomes and mitochondria, two organelles that are selectively targeted by autophagy, were elevated in PPD cases. Cellular deconvolution analysis discovered that EV mRNAs associated with PPD originated from monocytes and macrophages. Quantitative PCR analysis for four relevant genes in another cohort replicated these findings and confirmed that extracellular RNA levels are altered in PPD. We demonstrate that EV mRNA communication is robustly altered during pregnancy and the postpartum period in women who go on to develop PPD. Our work also establishes a direct link between reduced autophagy and PPD in patient samples. These data warrant investigating the feasibility of developing EV mRNA based biomarkers and therapeutic agents for PPD.

Human chorionic gonadotropin promotes murine Treg cells and restricts pregnancy-harmful proinflammatory Th17 responses.

An equilibrium between proinflammatory and anti-inflammatory immune responses is essential for maternal tolerance of the fetus throughout gestation. To study the participation of fetal tissue-derived factors in this delicate immune balance, we analyzed the effects of human chorionic gonadotropin (hCG) on murine Treg cells and Th17 cells in vitro, and on pregnancy outcomes, fetal and placental growth, blood flow velocities and remodeling of the uterine vascular bed in vivo. Compared with untreated CD4+CD25+ T cells, hCG increased the frequency of Treg cells upon activation of the LH/CG receptor. hCG, with the involvement of IL-2, also interfered with induced differentiation of CD4+ T cells into proinflammatory Th17 cells. In already differentiated Th17 cells, hCG induced an anti-inflammatory profile. Transfer of proinflammatory Th17 cells into healthy pregnant mice promoted fetal rejection, impaired fetal growth and resulted in insufficient remodeling of uterine spiral arteries, and abnormal flow velocities. Our works show that proinflammatory Th17 cells have a negative influence on pregnancy that can be partly avoided by in vitro re-programming of proinflammatory Th17 cells with hCG.

Human placenta-based genome-wide mRNA sequencing to identify TEK/IGF1/CSF1/ANGPT2 as crucial segments in the pathogenesis of pre-eclampsia.

Pre-eclampsia is a pregnancy-specific disease commonly occurring in late pregnancy and has always been threatening maternal and fetal lives, yet the etiology and pathogenesis of pre-eclampsia are still uncertain. To depict the overall changes of genes at the genome-wide level and identify potential biomarkers for early diagnosis of pre-eclampsia, we conducted this study by collecting placenta samples donated by six pregnancy women, among whom three healthy women were included as controls and three women were diagnosed with pre-eclampsia. The placental sample tissues were then subjected to high-throughput sequencing. Furthermore, we proceeded with bioinformatics analysis and formulated the hypothesis of pre-eclampsia development and verified the potential targets of pre-eclampsia by immunohistochemistry. Demographically, we found that the baseline characteristics of study subjects were highly homogeneous except for gestational weeks and blood pressure, where the blood pressure was higher and gestational weeks were shorter in the pre-eclampsia group (systolic blood pressure 123.33 ± 4.62 vs. 148.67 ± 3.79 mmHg, p = 0.046; diastolic blood pressure 79.00 ± 5.20 vs. 88.33 ± 2.89 mmHg, p = 0.068; gestational weeks 39.33 ± 1.03 vs. 35.76 ± 2.41, p = 0.050). Specific pathological changes were identified, shown as syncytial knots, fibrinoid necrosis, perivillous fibrin deposition, and vasculitis. For high-throughput sequencing, a total of 1,891 dysregulated genes were determined, of which 960 genes were downregulated and 931 genes were upregulated. The bioinformatics analysis indicated that these genes, with different molecular functions in different parts of cells, were primarily responsible for endothelium development and vascular process in the circulatory system, and more than 10 signaling pathways were involved. By focusing on the PI3K-Akt signaling pathway, Rap1 signaling pathway, and disease enrichment analysis item pre-eclampsia, TEK, CSF1, IGF1, and ANGPT2 were identified to promote the development of pre-eclampsia. After confirming the placental expression of these genes at the protein level, we proposed the pathogenesis of pre-eclampsia as follows: the downregulation of TEK, CSF1, IGF1, and ANGPT2 may inhibit trophoblast proliferation and affect the remodeling of spiral arteries, causing maternal and fetal malperfusion and impeding nutrient exchange, thereby leading to clinical manifestations of pre-eclampsia.

A non-redundant role of complement protein C1q in normal and adverse pregnancy

Complement component 1q (C1q) is the recognition molecule of the classical pathway of the complement system that can bind to an array of closely spaced antigen-bound immunoglobulin G (IgG) and IgM antibodies. In addition to its involvement in defence against a range of pathogens and clearance of apoptotic and necrotic cells, C1q has also been implicated in immune and non-immune homeostasis. C1q is locally produced by immune cells such as monocytes, macrophages, and dendritic cells. C1q is also synthesized by decidual endothelial cells, thus acting as a link between decidual cells and trophoblasts, as well as contributing to the remodelling of spiral arteries. Furthermore, C1q is produced by the extravillous trophoblasts (EVTs) invading the decidua. As a pro-angiogenic molecule, C1q is also important for normal placentation processes as it favors the active angiogenesis in the developing decidua. These observations have been validated by C1q gene knock-out mice which showed pre-eclampsia (PE)-like symptoms, characterized by hypertension, proteinuria, glomerular endotheliosis, and increased soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio, and increased oxidative stress. The role of C1q in normal and adverse human pregnancy is being studied extensively due to its absence or low level as a likely precipitating factor for the development of PE.

Porphyromonas gingivalis-mediated disruption in spiral artery remodeling is associated with altered uterine NK cell populations and dysregulated IL-18 and Htra1

Impaired spiral artery remodeling (IRSA) underpins the great obstetrical syndromes. We previously demonstrated that intrauterine infection with the periodontal pathogen, Porphyromonas gingivalis, induces IRSA in rats. Since our previous studies only examined the end stage of arterial remodeling, the aim of this study was to identify the impact of P. gingivalis infection on the earlier stages of remodeling. Gestation day (GD) 11 specimens, a transition point between trophoblast-independent remodeling and the start of extravillous trophoblast invasion, were compared to late stage GD18 tissues. P. gingivalis was found in decidual stroma of GD11 specimens that already had reduced spiral artery remodeling defined as smaller arterial lumen size, increased retention of vascular smooth muscle, and decreased invasion by extravillous trophoblasts. At GD11, P. gingivalis-induced IRSA coincided with altered uterine natural killer (uNK) cell populations, decreased placental bed expression of interleukin-18 (IL-18) with increased production of temperature requirement A1 (Htra1), a marker of oxidative stress. By GD18, placental bed IL-18 and Htra1 levels, and uNK cell numbers were equivalent in control and infected groups. However, infected GD18 placental bed specimens had decreased TNF + T cells. These results suggest disturbances in placental bed decidual stroma and uNK cells are involved in P. gingivalis-mediated IRSA.

Uterine natural killer cells and successful pregnancy: from mouse experiments to human physiology

Uterine natural killer (uNK) cells, a specific type of natural killer (NK) cells, are important cells at the foeto-maternal interface in humans as well as in mice. uNK cells are part of the innate lymphoid cells group 1. Especially in the mouse, but also in the rat, many in vivo studies have been performed to evaluate the role of uNK cells in placental development. These studies have shown that uNK cells are not indispensable to pregnancy, but that they play an important role in optimal decidual angiogenesis in early pregnancy, trophoblast invasion and spiral artery remodelling in the mouse placenta. Based on the mouse studies, various in vitro studies, as well as immunohistological studies of the human placenta from elective abortions, have shown that uNK cells have similar functions in the human placenta. In the present narrative review, the role of the uNK cells in the development of the mouse and rat placenta will be discussed first. Thereafter, studies on the role of human uNK cells in the human placenta will be reviewed and these studies will be discussed in the light of the knowledge on mouse uNK cells.

Gut Dysbiosis Promotes Preeclampsia by Regulating Macrophages and Trophoblasts.

Preeclampsia is one of the leading causes of maternal and perinatal morbidity and is characterized by hypertension, inflammation, and placental dysfunction. Gut microbiota plays key roles in inflammation and hypertension. However, its roles and mechanisms in preeclampsia have not been fully elucidated. 16S rRNA gene sequencing and targeted metabolomics were conducted on stool samples from 92 preeclamptic patients and 86 normal late-pregnant women. Then, fecal microbiota transplantation and in vitro and in vivo functional experiments were performed to explore the roles and mechanisms of gut microbiota in preeclampsia development. We revealed the gut microbiota dysbiosis in preeclamptic patients, including significant reductions in short-chain fatty acid-producing bacteria and short-chain fatty acids. The gut microbiota of preeclamptic patients significantly exacerbated pathologies and symptoms of preeclamptic rats, whereas the gut microbiota of healthy pregnant women had significant protective effects. Akkermansia muciniphila, propionate, or butyrate significantly alleviated the symptoms of preeclamptic rats. Mechanistically, they significantly promoted autophagy and M2 polarization of macrophages in placental bed, thereby suppressing inflammation. Propionate also significantly promoted trophoblast invasion, thereby improved spiral arterial remodeling. Additionally, we identified a marker set consisting of Akkermansia, Oscillibacter, and short-chain fatty acids that could accurately diagnose preeclampsia. Our study revealed that gut microbiota dysbiosis is an important etiology of preeclampsia. Gut microbiota and their active metabolites have great potential for the treatment and diagnosis of preeclampsia. Our findings enrich the gut-placenta axis theory and contribute to the development of microecological products for preeclampsia.

A novel regulated network mediated by downregulation HIF1A-AS2 lncRNA impairs placental angiogenesis by promoting ANGPTL4 expression in preeclampsia.

Preeclampsia (PE) is the predominant medical condition leading to maternal and fetal mortality, and the lack of effective treatment increases its risk to the public health. Among the numerous predisposing factors, the ineffectual remodeling of the uterine spiral arteries, which can induce abnormal placental angiogenesis, has been focused to solve the pathogenesis of PE. According to the preceding research results, abnormal expression of long non-coding RNAs (lncRNA)s could be associated with the pathological changes inducing PE. To be more specific, lncRNA HIF1A-AS2 was proposed for its potential to participate in the molecular mechanisms underlying PE. In vitro, in trophoblast cell lines HTR-8/SVneo and human umbilical vein endothelial cells HUVECs, HIF1A-AS2 knockdown inhibited cell proliferation, migration and tube formation. Mechanistically, transcription factor FOXP1 could regulate the expression of HIF1A-AS2. Moreover, a series of assays, including RNA pull down and mass spectrometry, RNA immunoprecipitation and chromatin immunoprecipitation assay, revealed that HIF1A-AS2 interacted with Lamin A/C (LMNA) to inhibit ANGPTL4 expression in trophoblast cells, thus further participating in the progression of PE. Taken together, these findings suggested that further analysis on HIF1A-AS2 could contribute to the development of prospective therapeutic strategy for PE.

Prevention of intrauterine fetal growth restriction by administrating C1q/TNF-related protein 6, a specific inhibitor of the alternative complement pathway.

The latest treatments do not sufficiently prevent miscarriage and fetal growth restriction (FGR) in pregnant women. Here, we assessed the effects of a human protein, CTRP6, that specifically inhibits the activation of the alternative complement pathway on miscarriage, fetal and placental development. Pregnant CBA/J mice mated with DBA/2 male mice as a model of spontaneous abortion and FGR were randomly divided into the control and CTRP6 groups. In the CTRP6 group, the mice were intravenously administered CTRP6 on days 4.5 and 6.5 post-conception (dpc). The abortion rate and fetal and placental weights on 14.5 dpc were examined. Remodeling of the spiral artery was also assessed. The abortion rate in the CTRP6 group (13%) was reduced compared to the control group (21%), but there was no statistical difference. The placental and fetal weights in the CTRP6 group were also heavier than those in the control (P < 0.05). Moreover, the thickness of the blood vessel wall in the CTRP6 group was significantly thinner than that in the control (P < 0.05) and comparable to that in the non-abortion model (CBA/J x BALB). The ratio of the inner-per-the-outer diameter of the spiral artery increased more in the CTRP6 group than that in the control (P < 0.05). As well, the Th1/Th2 cytokine ratio was significantly reduced by CTRP6 treatment. Taken together, the supplementation with a protein that regulates the alternative complement pathway in vivo improves FGR and promotes spiral artery remodeling in a mouse model of miscarriage and FGR.

The role of extravillous trophoblasts and uterine NK cells in vascular remodeling during pregnancy.

Successful embryo implantation requires both a receptive endometrium and competent blastocysts. After implantation, the maternal decidua undergoes a series of changes, including uterine spiral artery (SA) remodeling to accommodate the fetus and provide nutrients and oxygen for the fetus to survive. Uterine spiral arteries transform from small-diameter, high-resistance arteries to large-diameter and low-resistance arteries during pregnancy. This transformation includes many changes, such as increased permeability and dilation of vessels, phenotypic switching and migration of vascular smooth muscle cells (VSMCs), transient loss of endothelial cells (ECs), endovascular invasion of extravillous trophoblasts (EVTs), and presence of intramural EVT, which are regulated by uterine NK (uNK) cells and EVTs. In this review, we mainly focus on the separate and combined roles of uNK cells and EVTs in uterine SA remodeling in establishing and maintaining pregnancy. New insight into related mechanisms will help us better understand the pathogenesis of pregnancy complications such as recurrent pregnancy loss (RPL) and preeclampsia (PE).

Dynamic Changes in Uterine NK Cell Subset Frequency and Function Over the Menstrual Cycle and Pregnancy.

Uterine natural killer cells (uNK) play an important role in promoting successful pregnancy by regulating trophoblast invasion and spiral artery remodelling in the first trimester. Recently, single-cell RNA sequencing (scRNAseq) on first-trimester decidua showed that uNK can be divided into three subsets, which may have different roles in pregnancy. Here we present an integration of previously published scRNAseq datasets, together with novel flow cytometry data to interrogate the frequency, phenotype, and function of uNK1–3 in seven stages of the reproductive cycle (menstrual, proliferative, secretory phases of the menstrual cycle; first, second, and third trimester; and postpartum). We found that uNK1 and uNK2 peak in the first trimester, but by the third trimester, the majority of uNK are uNK3. All three subsets are most able to degranulate and produce cytokines during the secretory phase of the menstrual cycle and express KIR2D molecules, which allow them to interact with HLA-C expressed by placental extravillous trophoblast cells, at the highest frequency during the first trimester. Taken together, our findings suggest that uNK are particularly active and able to interact with placental cells at the time of implantation and that uNK1 and uNK2 may be particularly involved in these processes. Our findings are the first to establish how uNK frequency and function change dynamically across the healthy reproductive cycle. This serves as a platform from which the relationship between uNK function and impaired implantation and placentation can be investigated. This will have important implications for the study of subfertility, recurrent miscarriage, pre-eclampsia, and pre-term labour.