Embolization of the hypogastric artery after surgical ligation: A case series of two patients.

INTRODUCTION: The increasing incidence of obstetric complications, such as post-partum hemorrhage in the case of placenta accreta spectrum, calls for innovative and adapted therapeutic approaches. This presentation highlights the effectiveness of arterial embolization of the hypogastric artery, properly known as the internal iliac artery, in managing obstetric bleeding, even after initial surgical ligation. An approach never described in the literature. PRESENATION OF CASES: 1st Case: A 38-year-old patient, in her fourth pregnancy with two previous caesarean sections, was admitted for moderate metrorrhagia at 19 weeks gestation. Ultrasound showed a monofetal pregnancy at 17 WG with a 6 cm placental abruption and an anterior placenta with accretion signs. An emergency subtotal hysterectomy with triple Tsirulsikov arterial ligation was performed after transfusion. Due to persistent bleeding, bilateral hypogastric artery ligation and abdominal packing were added, but without improvement. The patient was referred for embolization after hemodynamic stabilization. The procedure was carried out successfully and no complications were reported. 2nd Case: A 35-year-old patient with vaginal bleeding from placenta accreta at 25 WG required hemostasis hysterectomy. Despite the procedure, bleeding continued, leading to bilateral hypogastric artery ligation and pelvic packing. The patient was hemodynamically stabilized and transferred for hypogastric artery ligation, which was successfully performed without complication. DISCUSSION: The role of interventional radiology in managing postpartum hemorrhage (PPH) is well established, with substantial literature supporting the benefits of uterine artery embolization as a lifesaving and often uterine-sparing procedure in PPH. While its indication for prevention is well-known, what about post-operatively? Our experience indicates that consulting a radiologist specializing in pelvic embolization can yield satisfactory outcomes despite technical difficulties. CONCLUSION: Embolization of the hypogastric arteries as well as embolization followed by surgical ligation of these arteries have been well described in the literature, the originality in our case reports is the embolization performed after surgical ligation which has not been described before according to our knowledge and which despite its technical difficulty can be a satisfactory alternative for the control of post-partum hemorrhage.

Twin reversed arterial perfusion (TRAP) sequence and placenta accreta.

TRAP sequence is a rare and severe complication of monozygotic pregnancies. We present the case of a 35 years old woman, diagnosed with a TRAP sequence for her second pregnancy, whose delivery was complicated of a severe hemorrhage from an unknown placenta accreta, making a hysterectomy necessary. If abnormal placentation is more frequent in multiple pregnancies, the physiopathology of TRAP sequence could explain the association with accreta placentation. One should keep in mind that a rare pathology can hide another.

Evolutionary Analysis of the Mammalian IL-17 Cytokine Family Suggests Conserved Roles in Female Fertility.

PROBLEM: The interleukin-17 (IL-17) family includes pro-inflammatory cytokines IL-17A-F with important roles in mucosal defence, barrier integrity and tissue regeneration. IL-17A can be dysregulated in fertility complications, including pre-eclampsia, endometriosis and miscarriage. Because mammalian subclasses (eutherian, metatherian, and prototherian) have different related reproductive strategies, IL-17 genes and proteins were investigated in the three mammalian classes to explore their involvement in female fertility. METHOD OF STUDY: Gene and protein sequences for IL-17s are found in eutherian, metatherian and prototherian mammals. Through synteny and multiple sequence protein alignment, the relationships among mammalian IL-17s were inferred. Publicly available datasets of early pregnancy stages and female fertility in therian mammals were collected and analysed to retrieve information on IL-17 expression. RESULTS: Synteny mapping and phylogenetic analyses allowed the classification of mammalian IL-17 family orthologs of human IL-17. Despite differences in their primary amino acid sequence, metatherian and prototherian IL-17s share the same tertiary structure as human IL-17s, suggesting similar functions. The analysis of available datasets for female fertility in therian mammals shows up-regulation of IL-17A and IL-17D during placentation. IL-17B and IL-17D are also found to be over-expressed in human fertility complication datasets, such as endometriosis or recurrent implantation failure. CONCLUSIONS: The conservation of the IL-17 gene and protein across mammals suggests similar functions in all the analysed species. Despite significant differences, the upregulation of IL-17 expression is associated with the establishment of pregnancy in eutherian and metatherian mammals. The dysregulation of IL-17s in human reproductive disorders suggests them as a potential therapeutic target.

Placental growth factor mediates pathological uterine angiogenesis by activating the NFAT5-SGK1 signaling axis in the endometrium: implications for preeclampsia development.

After menstruation the uterine spiral arteries are repaired through angiogenesis. This process is tightly regulated by the paracrine communication between endometrial stromal cells (EnSCs) and endothelial cells. Any molecular aberration in these processes can lead to complications in pregnancy including miscarriage or preeclampsia (PE). Placental growth factor (PlGF) is a known contributing factor for pathological angiogenesis but the mechanisms remain poorly understood. In this study, we investigated whether PlGF contributes to pathological uterine angiogenesis by disrupting EnSCs and endothelial paracrine communication. We observed that PlGF mediates a tonicity-independent activation of nuclear factor of activated T cells 5 (NFAT5) in EnSCs. NFAT5 activated downstream targets including SGK1, HIF-1α and VEGF-A. In depth characterization of PlGF - conditioned medium (CM) from EnSCs using mass spectrometry and ELISA methods revealed low VEGF-A and an abundance of extracellular matrix organization associated proteins. Secreted factors in PlGF-CM impeded normal angiogenic cues in endothelial cells (HUVECs) by downregulating Notch-VEGF signaling. Interestingly, PlGF-CM failed to support human placental (BeWo) cell invasion through HUVEC monolayer. Inhibition of SGK1 in EnSCs improved angiogenic effects in HUVECs and promoted BeWo invasion, revealing SGK1 as a key intermediate player modulating PlGF mediated anti-angiogenic signaling. Taken together, perturbed PlGF-NFAT5-SGK1 signaling in the endometrium can contribute to pathological uterine angiogenesis by negatively regulating EnSCs-endothelial crosstalk resulting in poor quality vessels in the uterine microenvironment. Taken together the signaling may impact on normal trophoblast invasion and thus placentation and, may be associated with an increased risk of complications such as PE.

A Narrative Review on the Pathophysiology of Preeclampsia.

Preeclampsia (PE) is a multifactorial pregnancy disorder characterized by hypertension and proteinuria, posing significant risks to both maternal and fetal health. Despite extensive research, its complex pathophysiology remains incompletely understood. This narrative review aims to elucidate the intricate mechanisms contributing to PE, focusing on abnormal placentation, maternal systemic response, oxidative stress, inflammation, and genetic and epigenetic factors. This review synthesizes findings from recent studies, clinical trials, and meta-analyses, highlighting key molecular and cellular pathways involved in PE. The review integrates data on oxidative stress biomarkers, angiogenic factors, immune interactions, and mitochondrial dysfunction. PE is initiated by poor placentation due to inadequate trophoblast invasion and improper spiral artery remodeling, leading to placental hypoxia. This triggers the release of anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), causing widespread endothelial dysfunction and systemic inflammation. Oxidative stress, mitochondrial abnormalities, and immune dysregulation further exacerbate the condition. Genetic and epigenetic modifications, including polymorphisms in the Fms-like tyrosine kinase 1 (FLT1) gene and altered microRNA (miRNA) expression, play critical roles. Emerging therapeutic strategies targeting oxidative stress, inflammation, angiogenesis, and specific molecular pathways like the heme oxygenase-1/carbon monoxide (HO-1/CO) and cystathionine gamma-lyase/hydrogen sulfide (CSE/H2S) pathways show promise in mitigating preeclampsia's effects. PE is a complex disorder with multifactorial origins involving abnormal placentation, endothelial dysfunction, systemic inflammation, and oxidative stress. Despite advances in understanding its pathophysiology, effective prevention and treatment strategies remain limited. Continued research is essential to develop targeted therapies that can improve outcomes for both mothers and their babies.

Behind the Curtain of Abnormal Placentation in Pre-Eclampsia: From Molecular Mechanisms to Histological Hallmarks.

Successful human pregnancy needs several highly controlled steps to guarantee an oocyte's fertilization, the embryo's pre-implantation development, and its subsequent implantation into the uterine wall. The subsequent placenta development ensures adequate fetal nutrition and oxygenation, with the trophoblast being the first cell lineage to differentiate during this process. The placenta sustains the growth of the fetus by providing it with oxygen and nutrients and removing waste products. It is not surprising that issues with the early development of the placenta can lead to common pregnancy disorders, such as recurrent miscarriage, fetal growth restriction, pre-eclampsia, and stillbirth. Understanding the normal development of the human placenta is essential for recognizing and contextualizing any pathological aberrations that may occur. The effects of these issues may not become apparent until later in pregnancy, during the mid or advanced stages. This review discusses the process of the embryo implantation phase, the molecular mechanisms involved, and the abnormalities in those mechanisms that are thought to contribute to the development of pre-eclampsia. The review also covers the histological hallmarks of pre-eclampsia as found during the examination of placental tissue from pre-eclampsia patients.

Vitamin C inactivates c-Jun N-terminal kinase to stabilize heart and neural crest derivatives expressed 1 (Hand1) in regulating placentation and maintenance of pregnancy.

Vitamin C (VC) serves as a pivotal nutrient for anti-oxidation process, metabolic responses, and stem cell differentiation. However, its precise contribution to placenta development and gestation remains obscure. Here, we demonstrated that physiological levels of VC act to stabilize Hand1, a key bHLH transcription factor vital for the development trajectory of trophoblast giant cell (TGC) lineages, thereby promoting the differentiation of trophoblast stem cells into TGC. Specifically, VC administration inactivated c-Jun N-terminal kinase (JNK) signaling, which directly phosphorylates Hand1 at Ser48, triggering the proteasomal degradation of Hand1. Conversely, a loss-of-function mutation at Ser48 on Hand1 not only significantly diminished both intrinsic and VC-induced stabilization of Hand1 but also underscored the indispensability of this residue. Noteworthy, the insufficiency of VC led to severe defects in the differentiation of diverse TGC subtypes and the formation of labyrinth's vascular network in rodent placentas, resulting in failure of maintenance of pregnancy. Importantly, VC deficiency, lentiviral knockdown of JNK or overexpression of Hand1 mutants in trophectoderm substantially affected the differentiation of primary and secondary TGC in E8.5 mouse placentas. Thus, these findings uncover the significance of JNK inactivation and consequential stabilization of Hand1 as a hitherto uncharacterized mechanism controlling VC-mediated placentation and perhaps maintenance of pregnancy.

Evidence for metabolism of creatine by the conceptus, placenta, and uterus for production of ATP during conceptus development in pigs.

In pigs, the majority of embryonic mortality occurs when free-floating conceptuses (embryos/fetuses and associated placental membranes) elongate and the uterine-placental interface undergoes folding and develops areolae. Both periods involve proliferation, migration, and changes in morphology of cells that require ATP. We hypothesize that insufficient ATP in conceptus and uterine tissues contributes to conceptus loss in pigs. Creatine is stored in cells as phosphocreatine (PCr) for ATP regeneration through the creatine (Cr)-creatine kinase (CK)-PCr pathway. However, the expression of components of this pathway in pigs has not been examined throughout gestation. Results of qPCR analyses indicated increases in AGAT, GAMT, CKM, CKB, and SLC6A8 mRNAs in elongating porcine conceptuses and immunofluorescence microscopy localized GAMT, CKM, and CKB proteins to the trophectoderm of elongating conceptuses, to the columnar chorionic epithelial cells at the bottom of chorioallantoic troughs, and to endometrial luminal epithelium (LE) at the tops of the endometrial ridges of uterine-placental folds on Days 40, 60, and 90 of gestation. GAMT protein is expressed in endometrial LE at the uterine-placental interface, but immunostaining is more intense in LE at the bottoms of the endometrial ridges. Results of this study indicate that key elements of the pathway for creatine metabolism are expressed in cells of the conceptus, placenta, and uterus for potential production of ATP during two timepoints in pregnancy with a high demand for energy; elongation of the conceptus for implantation and development of uterine-placental folding during placentation.

Unravelling the oxygen factor - An investigation of transcriptional activation of hypoxia associated placental angiogenesis in recurrent pregnancy loss (RPL) patients from Assam, India.

INTRODUCTION: Recurrent pregnancy loss (RPL) is defined as the spontaneous loss of two or more consecutive pregnancies before 20 weeks of gestation, and affects 7.46 % of the Indian population. About 40-50 % of RPL cases are idiopathic making it a therapeutic challenge for clinicians. This study focuses on elucidating the role of hypoxia-associated placental angiogenesis in these idiopathic RPL cases. METHODS: Whole blood and product of conception (POCs) were collected from RPL patients (N = 87) and cases of voluntary abortions (medically terminated pregnancy, MTP; n = 110) as controls with informed consent. Serum separated from whole blood was used to study the ROS-antioxidant status in the cases and controls through colorimetric assays and ELISA. The mRNA extracted from placental tissue samples were used to determine the hypoxic and angiogenic status in cases and controls through real time PCR. Statistical analysis was also carried out to correlate the differential hypoxic status between RPL and MTP cohorts with the expression of angiogenic factors (VEGFA, VEGFR1 and VEGFR2). RESULTS: HIF1α mRNA expression was found to be upregulated in the RPL cases. While the serum levels of H2O2 (p = 0.012), guanine oxides and lipid hydroperoxides (LPO) were increased in the RPL cases, reduced glutathione (GSH) was found to be significantly decreased (p = 0.012). Additionally, AUROC analysis also shows an excellent discriminatory ability of 0.850 for serum H2O2 levels. VEGF-A and VEGF-R1 mRNA expression was also found to be downregulated in the RPL cases compared to MTP. DISCUSSION: This study indicates that increased oxidative stress may lead to aberrations in the VEGF pathway resulting in improper placentation in RPL cases, and subsequently, pregnancy loss.

Predictive Value and Limitations of the Placenta Accreta Index: A Systematic Review.

Our systematic review highlights that multiparametric PAI score assessment is a consistent tool with high sensitivity and specificity for prenatal prediction for placenta accreta spectrum (PAS) in high-risk population with anterior placenta previa or low-lying placenta and prior cesarean deliveries. A systematic search was conducted on November 1, 2022, of MEDLINE via PubMed, Scopus, Web of Science Core Collection, Cochrane Library, and Google Scholar to identify relevant studies (PROSPERO ID # CRD42022368211). A total of 11 articles met our inclusion criteria, representing the data of a total of 1,044 cases. Women with PAS had an increased mean PAI total score, compared to those without PAS. Limitations of the PAI are most studies were conducted in developing countries in high-risk population which limit the global generalizability of findings. Heterogeneity of reported data did not allow to perform meta-analysis.

Cited2 is a key regulator of placental development and plasticity.

The biology of trophoblast cell lineage development and placentation is characterized by the involvement of several known transcription factors. Central to the action of a subset of these transcriptional regulators is CBP-p300 interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2). CITED2 acts as a coregulator modulating transcription factor activities and affecting placental development and adaptations to physiological stressors. These actions of CITED2 on the trophoblast cell lineage and placentation are conserved across the mouse, rat, and human. Thus, aspects of CITED2 biology in hemochorial placentation can be effectively modeled in the mouse and rat. In this review, we present information on the conserved role of CITED2 in the biology of placentation and discuss the use of CITED2 as a tool to discover new insights into regulatory mechanisms controlling placental development.

Prenatal triphenyl phosphate exposure impairs placentation and induces preeclampsia-like symptoms in mice.

Triphenyl phosphate (TPhP) is an organophosphate flame retardant that is widely used in many commercial products. The United States Environmental Protection Agency has listed TPhP as a priority compound that requires health risk assessment. We previously found that TPhP could accumulate in the placentae of mice and impair birth outcomes by activating peroxisome proliferator-activated receptor gamma (PPARγ) in the placental trophoblast. However, the underlying mechanism remains unknown. In this study, we used a mouse intrauterine exposure model and found that TPhP induced preeclampsia (PE)-like symptoms, including new on-set gestational hypertension and proteinuria. Immunofluorescence analysis showed that during placentation, PPARγ was mainly expressed in the labyrinth layer and decidua of the placenta. TPhP significantly decreased placental implantation depth and impeded uterine spiral artery remodeling by activating PPARγ. The results of the in vitro experiments confirmed that TPhP inhibited extravillous trophoblast (EVT) cell migration and invasion by activating PPARγ and inhibiting the PI3K-AKT signaling pathway. Overall, our data demonstrated that TPhP could activate PPARγ in EVT cells, inhibit cell migration and invasion, impede placental implantation and uterine spiral artery remodeling, then induce PE-like symptom and impair birth outcomes. Although the exposure doses used in this study was several orders of magnitude higher than human daily intake, our study highlights the placenta as a potential target organ of TPhP worthy of further research.

Customizing EV-CATCHER to Purify Placental Extracellular Vesicles from Maternal Plasma to Detect Placental Pathologies.

Placenta Accreta Spectrum (PAS) is a life-threatening condition in which placental trophoblastic cells abnormally invade the uterus, often up to the uterine serosa and, in extreme cases, tissues beyond the uterine wall. Currently, there is no clinical assay for the non-invasive detection of PAS, and only ultrasound and MRI can be used for its diagnosis. Considering the subjectivity of visual assessment, the detection of PAS necessitates a high degree of expertise and, in some instances, can lead to its misdiagnosis. In clinical practice, up to 50% of pregnancies with PAS remain undiagnosed until delivery, and it is associated with increased risk of morbidity/mortality. Although many studies have evaluated the potential of fetal biomarkers circulating in maternal blood, very few studies have evaluated the potential of circulating placental extracellular vesicles (EVs) and their miRNA contents for molecular detection of PAS. Thus, to purify placental EVs from maternal blood, we customized our robust ultra-sensitive immuno-purification assay, termed EV-CATCHER, with a monoclonal antibody targeting the membrane Placental Alkaline Phosphatase (PLAP) protein, which is unique to the placenta and present on the surface of placental EVs. Then, as a pilot evaluation, we compared the miRNA expression profiles of placental EVs purified from the maternal plasma of women diagnosed with placenta previa (controls, n = 16); placenta lying low in uterus but not invasive) to those of placental EVs purified from the plasma of women with placenta percreta (cases, n = 16), PAS with the highest level of invasiveness. Our analyses reveal that miRNA profiling of PLAP+ EVs purified from maternal plasma identified 40 differentially expressed miRNAs when comparing these two placental pathologies. Preliminary miRNA pathway enrichment and gene ontology analysis of the top 14 upregulated and top nine downregulated miRNAs in PLAP+ EVs, purified from the plasma of women diagnosed with placenta percreta versus those diagnosed with placenta previa, suggests a potential role in control of cellular invasion and motility that will require further investigation.

A rare case of adventitious placentation (diffuse semi-placenta) in a Jersey cow.

Placental abnormalities more frequently occur during pregnancy of somatic cell clones and may lead to pregnancy loss or dystocia. Adventitious placentation, or diffuse semi-placenta, is determined by the development of areas of accessory placentation between the cotyledons due to the abnormal growth of placentomes.After a full-term pregnancy, a 3-year-old Jersey heifer was referred for dystocia which resulted in the delivery of a dead calf. The cause of dystocia was found to be foetal malposition, while the placenta was physiologically expelled after dystocia resolution.Grossly, cotyledons appeared reduced in size and number in one placental horn, while the surface of the other horn was covered with microplacentomes. Numerous villous structures without trophoblastic coating were highlighted after histopathology. The dominant sign was an inflammatory reaction. The findings were consistent with inter-cotyledonal placentitis, which led to adventitial placentation.Diffuse semi-placenta compensates for the inadequate development of placentomes and may occur as a congenital or acquired defect. The outcome depends on its severity: in the worst scenario, pregnancy may not proceed beyond midterm and may be complicated by hydrallantois. In the case under examination, the dimensions of the cotyledons (from 2 to 10 cm) allowed for the natural course of pregnancy.

Phylogenetic analysis of viviparity, matrotrophy, and other reproductive patterns in chondrichthyan fishes.

The reproductive diversity of extant cartilaginous fishes (class Chondrichthyes) is extraordinarily broad, reflecting more than 400 million years of evolutionary history. Among their many notable reproductive specialisations are viviparity (live-bearing reproduction) and matrotrophy (maternal provision of nutrients during gestation). However, attempts to understand the evolution of these traits have yielded highly discrepant conclusions. Here, we compile and analyse the current knowledge on the evolution of reproductive diversity in Chondrichthyes with particular foci on the frequency, phylogenetic distribution, and directionality of evolutionary changes in their modes of reproduction. To characterise the evolutionary transformations, we amassed the largest empirical data set of reproductive parameters to date covering nearly 800 extant species and analysed it via a comprehensive molecular-based phylogeny. Our phylogenetic reconstructions indicated that the ancestral pattern for Chondrichthyes is 'short single oviparity' (as found in extant holocephalans) in which females lay successive clutches (broods) of one or two eggs. Viviparity has originated at least 12 times, with 10 origins among sharks, one in batoids, and (based on published evidence) another potential origin in a fossil holocephalan. Substantial matrotrophy has evolved at least six times, including one origin of placentotrophy, three separate origins of oophagy (egg ingestion), and two origins of histotrophy (uptake of uterine secretions). In two clades, placentation was replaced by histotrophy. Unlike past reconstructions, our analysis reveals no evidence that viviparity has ever reverted to oviparity in this group. Both viviparity and matrotrophy have arisen by a variety of evolutionary sequences. In addition, the ancestral pattern of oviparity has given rise to three distinct egg-laying patterns that increased clutch (brood) size and/or involved deposition of eggs at advanced stages of development. Geologically, the ancestral oviparous pattern arose in the Paleozoic. Most origins of viviparity and matrotrophy date to the Mesozoic, while a few that are represented at low taxonomic levels are of Cenozoic origin. Coupled with other recent work, this review points the way towards an emerging consensus on reproductive evolution in chondrichthyans while offering a basis for future functional and evolutionary analyses. This review also contributes to conservation efforts by highlighting taxa whose reproductive specialisations reflect distinctive evolutionary trajectories and that deserve special protection and further investigation.

Dominance of Pro-Inflammatory Cytokines Over Anti-Inflammatory Ones in Placental Bed of Creta Cases.

Objective: The objective of the study is to investigate changes occurring in key inflammatory cytokines at molecular level (including genetic and protein) in placental bed of placenta creta compared to that of normal placenta and their correlation to interstitial extravillous trophoblasts (EVT) number. Subjects and Methods: Case-control study including placentas of patients with invasive placentation (creta placentas, n = 19) compared with those of normal placentation (n = 19). Besides routine histology and immunocytochemistry detection (cytokeratin-7 [CK-7]), addition to biochemical evaluation of expression of various cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), IL6, IL-1RA, IL-8, IL-10, and IL-13 was carried out. Results: Routine histological examination of placentas of creta cases revealed CK-7+ extravillous trophoblasts (EVT) penetrating deeply the myometrium with various histopathological arrangements and trophoblastic vascular invasion of the deep myometrial blood vessels. A significant increase (P < 0.05) in the mRNA expression of TNF-α, IL-1 ß, and IL6 with an insignificant decrease in placental bed IL-1RA, IL-8, IL-10, and IL-13 was observed in creta cases compared to the control ones. A corresponding significant increase was detected in the protein levels of TNF-α, IL-1 ß, and IL-6 as well as an insignificant decrease in placental bed IL-1RA, IL-8, IL-10, and IL-13 in creta cases compared to the normal ones. Moreover, we displayed a significant positive correlation (P < 0.05) between interstitial EVT number and mRNA expression of almost all pro-inflammatory cytokines with negative but insignificant correlation with anti-inflammatory cytokines in creta cases. Conclusion: The upregulated pro-inflammatory cytokines and the correlation of their expression with the increased interstitial EVT provide a supporting evidence of their potentially more relevant role in the development of placenta creta than the anti-inflammatory ones.

Uterine macrophages and NK cells exhibit population and gene-level changes after implantation but maintain pro-invasive properties.

Introduction: Prior to pregnancy, hormonal changes lead to cellular adaptations in the endometrium allowing for embryo implantation. Critical for successful pregnancy establishment, innate immune cells constitute a significant proportion of uterine cells prior to arrival of the embryo and throughout the first trimester in humans and animal models. Abnormal uterine immune cell function during implantation is believed to play a role in multiple adverse pregnancy outcomes. Current work in humans has focused on uterine immune cells present after pregnancy establishment, and limited in vitro models exist to explore unique functions of these cells. Methods: With single-cell RNA-sequencing (scRNAseq), we comprehensively compared the human uterine immune landscape of the endometrium during the window of implantation and the decidua during the first trimester of pregnancy. Results: We uncovered global and cell-type-specific gene signatures for each timepoint. Immune cells in the endometrium prior to implantation expressed genes associated with immune metabolism, division, and activation. In contrast, we observed widespread interferon signaling during the first trimester of pregnancy. We also provide evidence of specific inflammatory pathways enriched in pre- and post-implantation macrophages and natural killer (NK) cells in the uterine lining. Using our novel implantation-on-a-chip (IOC) to model human implantation ex vivo, we demonstrate for the first time that uterine macrophages strongly promote invasion of extravillous trophoblasts (EVTs), a process essential for pregnancy establishment. Pre- and post-implantation uterine macrophages promoted EVT invasion to a similar degree as pre- and post-implantation NK cells on the IOC. Conclusions: This work provides a foundation for further investigation of the individual roles of uterine immune cell subtypes present prior to embryo implantation and during early pregnancy, which will be critical for our understanding of pregnancy complications associated with abnormal trophoblast invasion and placentation.

Angiogenic factors and the lectin pathway of complement in women with secondary recurrent pregnancy loss.

The poor remodeling of placental spiral arteries seen in preeclampsia is also discussed to contribute to recurrent pregnancy loss (RPL) preceded by abnormal angiogenesis and excessive complement activation. Low levels of Mannose-binding-lectin (MBL), a pattern recognition molecule (PRM) of the lectin pathway, have been found in women with RPL. We propose that pregnancy loss is connected to defective angiogenesis with reperfusion damage in the placenta and decreased levels of PRM in the lectin pathway in women with RPL. In this cohort study, we investigate the angiogenic factors and the lectin complement pathway in early pregnancy and their time-dependent relationship with pregnancy outcomes in 76 women with secondary RPL (sRPL) who have at least four prior pregnancy losses and a live birth. We evaluated levels of Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Vascular Endothelial Growth Factor (VEGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PRMs, MBL, ficolin-1, -2, -3 and an additional soluble PRM, Pentraxin-3, during the 5th, 6th, and 7th gestational weeks. Our results showed that, compared to live births, pregnancies that ended in loss were associated with elevated VEGF levels and decreased levels of the Ang-2/Ang-1 ratio. Also, increasing levels of ficolin-2 were significantly associated with pregnancy loss, with MBL showing no association. Our research suggests that women with sRPL may have inadequate placentation with impaired angiogenesis in pregnancies ending in a loss.

Inositol-Exchange Activity in Human Primordial Placenta.

Human placenta is an intensively growing tissue. Phosphatidylinositol (PI) and its derivatives are part of the signaling pathway in the regulation of trophoblast cell differentiation. There are two different enzymes that take part in the direct PI synthesis: phosphatidylinositol synthase (PIS) and inositol exchange enzyme (IE). The presence of PIS is known in the human placenta, but IE activity has not been documented before. In our study, we describe the physiological properties of the two enzymes in vitro. PIS and IE were studied in different Mn2+ and Mg2+ concentrations that enabled us to separate the individual enzyme activities. Enzyme activity was measured by incorporation of 3[H]inositol in human primordial placenta tissue or microsomes. Optimal PIS activity was achieved between 0.5 and 2.0 mM Mn2+ concentration, but higher concentrations inhibit enzyme activity. In the presence of Mg2+, the enzyme activity increases continuously up to a concentration of 100 mM. PIS was inhibited by nucleoside di- and tri-phosphates. PI production increases between 0.1 and 10 mM Mn2+ concentration. The incorporation of [3H]inositol into PI increased by 57% when adding stabile GTP analog. The described novel pathway of inositol synthesis may provide an additional therapeutic approach of inositol supplementation before and during pregnancy.