Endovascular Invasion Research Articles

Emerging Roles of the Complement System at Foeto-maternal Interface

The complement system is one of the major components of humoral innate immunity, acting as one of the first lines of defence against microbes, but new roles in inflammatory and immunological processes are emerging. The placenta undergoes an intense process of tissue remodelling which leads to the activation of the complement (C) system resulting in the release of potentially destructive activation products that need to be neutralized. The protection of the foetus against maternal C activation products is achieved by the surface expression of regulators. The liver is the main source of the plasma C components although extra-hepatic synthesis in several tissues and organs has been documented. The data collected recently indicate that trophoblast cells are able to secrete C3 and C4 and the recognition molecule C1q, contributing to the local synthesis at the placental level. Besides trophoblast cells, decidual endothelial cells acquire the ability to synthesize and express C1q on the cell surface. All these observations support the role of C1q in the placental development and its importance in trophoblast endovascular and interstitial invasion. In conclusion it is increasingly evident that a new role of complement and in particular C1q in the processes of tissue homeostasis as well as is in inflammation and infection is now emerging.

Bizarre expression of tissue inhibitor of metalloproteinase-3 in feto–maternal interface caused gestational hypertension in mice model

Department of Obstetrics and Gynaecololgy, Osaka University Graduate School of Medicine, Suita, Osaka, Japan Preeclampsia (PE) is believed to result from abnormal placentation in early pregnancy. Shallow endovascular cytotrophoblast invasion and endothelial cell dysfunction are two key features in the pathogenesis of PE. Matrix metalloproteinase-9 (MMP-9) is crucial for the invasive ability of trophoblast cells during placentation. Tissue inhibitor of metalloproteinase-3 (TIMP-3), which is known as a potent inhibitor of MMP-9, also plays a role in regulating trophoblast invasion to the uterine endometrium. However little is known about the role of matrix metalloproteases and their inhibitors on regulation of maternal and fetal circulation. In the present study, we applied in vivo gene transfer system with hemagglutinating virus of Japan envelope (HVJ-E) vector into feto–maternal interface of pregnant mice on day 6.5 post coitus (pc), during the period of placental development. Overexpression of TIMP3 cDNA suppressedMMP-9 activity in the uterus. Maternal systolic blood pressure significantly rose from day 14.5 pc to parturition. The fetus and the placentae were significantly smaller, and serum soluble fms-like tyrosine kinase (Flt)-1 and soluble endoglin levelswere significantlyhigher after TIMP-3 treatment than in control mice. These data suggest that the balance between matrix metalloprotease and its inhibitor may play a pivotal role in determining feto/maternal circulation.

448 Targeting the p53 tumour suppressor activity in Glioblastomas using small molecule MDM2-inhibitor

Preeclampsia, particularly the severe cases that occur early in pregnancy, is associated with defects in the (placental) cytotrophoblast differentiation pathway that leads to uterine invasion. At a morphologic level, interstitial invasion often is shallow. Perhaps more significantly, endovascular invasion, particularly the arterial component, is rudimentary. The latter defect is thought to lead to hypoperfusion of the placenta. At a molecular level, these defects are associated with particular deficits in the differentiation process whereby cytotrophoblasts—epithelial cells of ectodermal origin—assume vascular-like properties. Until recently, the question was how the latter defects could lead to the maternal symptoms of this condition. Now a possible link in the form of preeclampsia-associated changes in placental production of vasculogenic/angiogenic substances and their inhibitors has been discovered. It is likely that this new paradigm will improve both diagnosis and treatment of this life-threatening pregnancy complication.

Endovascular Trophoblast Invasion, Spiral Artery Remodelling and Uteroplacental Haemodynamics in a Transgenic Rat Model of Pre-eclampsia

The aim of the present study was to evaluate the depth of endovascular trophoblast invasion and associated remodelling of spiral arteries in a transgenic model of pre-eclampsia in the rat, a species showing a comparable deep invasion during normal pregnancy as the human. Pre-eclamptic (PE) transgenic rats (TGR) (hAngiotensinogen ♀ × hRenin ♂) and non-PE reversely mated (RM) TGR rats were compared to normal Sprague–Dawley rats (C). Day 18 implantation sites were collected and the presence of endovascular trophoblast, fibrinoid, endothelial and smooth muscle cells were evaluated in spiral arteries in three parallel layers in the mesometrial triangle using an image analysis system (KS-400). In a separate group of animals peak-systolic and end-diastolic velocities were measured by Doppler in uterine and arcuate arteries, and the resistance indices (RI) were calculated. In PE and RM rats, the entire mesometrial triangle contained significantly more endovascular trophoblast and vascular fibrinoid deposits than the C group. No difference was found between the groups in the overall amount of smooth muscle surrounding the lumen, but in the PE and RM groups significantly more muscle was present in parts of the contours covered by trophoblast. There was significantly less CD31-positive endothelium in the total lumen contours of the PE and RM groups than in the C group, but in parts of the contours covered by trophoblast more residual endothelium was present in both TGR groups. Comparison of the three layers indicated deeper invasion in both the PE and RM groups than in the C group. By Doppler analysis of the proximal uterine artery the RI was found to be significantly lower in the PE and the RM group than in the C group. In the arcuate artery, the RI was significantly lower in the PE group as compared to the RM and C groups. We conclude that in this transgenic PE rat model there is deeper endovascular invasion of spiral arteries and decreased RI of uterine arteries at day 18 of pregnancy.

Comparative analysis of maternal-fetal interface in preeclampsia and preterm labor

The maternal-fetal interface, a chimeric structure, is formed when fetal cytotrophoblasts (CTBs) from the placenta invade the uterine wall and its resident vasculature. In preeclampsia (PE), interstitial and endovascular invasion are often shallow, and fewer spiral arterioles are breached in toto. Our previous work has shown that faulty CTB differentiation to an invasive phenotype is a contributing factor. Here, we have tested the hypothesis that the constellation of morphological and molecular defects that are associated with PE are unique to this condition. Specifically, we have compared the histology of the maternal-fetal interface and CTB expression of stage-specific antigens in PE and in preterm labor (PTL) with or without inflammation. In the absence of inflammation, biopsies obtained after PTL were near normal at histological and molecular levels. In accord with previously published data, PE had severe negative effects on the endpoints analyzed. Biopsies obtained after PTL with inflammation had an intermediate phenotype. Our results suggest that the maternal-fetal interface from cases of PTL without inflammation can be used for comparative purposes, e.g., as age-matched controls, in studies of the effects of PE on cells in this region.

Increased Apoptosis in First Trimester Extravillous Trophoblasts from Pregnancies at Higher Risk of Developing Preeclampsia

Preeclampsia complicates 5 to 10% of pregnancies and is a leading cause of maternal and fetal mortality and morbidity. Although the cause is unknown, inadequate invasion and remodeling of maternal uterine arteries by extravillous trophoblasts (EVTs) in the first trimester is a common feature. Uterine spiral artery resistance as detected by Doppler ultrasound is commonly used in the second trimester to identify pregnancies destined to develop preeclampsia. Correlation between high uterine resistance and the failure of trophoblast invasion has been reported as early as 12 weeks. However, the reason for this failure has not been established. Understanding the processes involved would significantly improve our diagnostic potential. In this study, we correlated increased first trimester uterine artery resistance with a biological abnormality in trophoblast function. EVTs derived from high-resistance pregnancies were more sensitive to apoptotic stimuli than those from normal-resistance pregnancies. Survival of EVTs from high-resistance pregnancies could be increased by nitric oxide, whereas inhibition of nitric oxide in cells from normal-resistance pregnancies increased apoptotic sensitivity. This predates the onset of symptoms by several weeks and provides evidence for a mechanism responsible for the incomplete uterine vessel remodeling and the differences in artery resistance between preeclamptic and normal pregnancies.

Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus

How the fetus escapes rejection by the maternal immune system remains one of the major unsolved questions in transplantation immunology. Using a system to visualize both CD4+ and CD8+ T cell responses during pregnancy in mice, we find that maternal T cells become aware of the fetal allograft exclusively through "indirect" antigen presentation, meaning that T cell engagement requires the uptake and processing of fetal/placental antigen by maternal APCs. This reliance on a relatively minor allorecognition pathway removes a major threat to fetal survival, since it avoids engaging the large number of T cells that typically drive acute transplant rejection through their ability to directly interact with foreign MHC molecules. Furthermore, CD8+ T cells that indirectly recognize fetal/placental antigen undergo clonal deletion without priming for cytotoxic effector function and cannot induce antigen-specific fetal demise even when artificially activated. Antigen presentation commenced only at mid-gestation, in association with the endovascular invasion of placental trophoblasts and the hematogenous release of placental debris. Our results suggest that limited pathways of antigen presentation, in conjunction with tandem mechanisms of immune evasion, contribute to the unique immunological status of the fetus. The pronounced degree of T cell ignorance of the fetus also has implications for the pathophysiology of immune-mediated early pregnancy loss.

Pathophysiology of the Clinical Manifestations of Preeclampsia

Five to 7% of all pregnancies are complicated by preeclampsia. Proteinuria and hypertension dominate the clinical picture, because the chief target organ is the kidney (glomerular endotheliosis). The pathogenesis of preeclampsia is complex; numerous genetic, immunologic, and environmental factors interact. It has been suggested that preeclampsia is a two-stage disease (1). The first stage is asymptomatic, characterized by abnormal placental development during the first trimester resulting in placental insufficiency and the release of excessive amounts of placental materials into the maternal circulation. This in turn leads to the second, symptomatic stage, wherein the pregnant woman develops characteristic hypertension, renal impairment, and proteinuria and is at risk for the HELLP syndrome (hemolysis, elevated liver function enzymes and low platelets), eclampsia, and other end-organ damage. This review focuses on the pathophysiology of stages 1 and 2 and then considers the potential that changes in soluble angiogenic factors may underlie much of the disease process. On the basis of the observation that the only definitive cure for preeclampsia is delivery of the placenta and that women who experience a molar pregnancy, in which a placenta develops without a fetus, frequently develop severe preeclampsia, it is reasonable to assume that the placenta plays a central role in the pathogenesis of the disease. Pathologic examination of placentas from preeclamptic pregnancies generally reveals placental infarcts and sclerotic narrowing of arteries and arterioles, with characteristic diminished endovascular invasion by cytotrophoblasts and inadequate remodeling of the uterine spiral arterioles (2). Although gross pathologic changes are not always seen in the placentas of women with preeclampsia, placental profiles including abnormal uterine artery Doppler and placental morphology have been used to identify a subset from a cohort of high-risk women who go on to develop the syndrome (3). Uterine artery Doppler studies that assess the pulsatility index (PI) reveal increased …

Angiogenesefaktoren in der Schwangerschaft: Indikatoren für die Präeklampsie

Preeclampsia is a major cause of maternal, fetal and neonatal mortality worldwide. The etiology of preeclampsia is still unclear. Currently, the inadequate transformation of the smooth muscle cells of spiral arteries in the placental bed caused by an insufficient endovascular invasion of the trophoblast is considered to be the major reason for the development of preeclampsia. This insufficient invasion seems to lead to altered placental angiogenesis which thus has causal importance for the development of preeclampsia. Vascular endothelial growth factor (VEGF) and placental growth factor (PLGF) are the most important angiogenic factors with regulatory functions for placental vessel development. In preeclamptic pregnancies the expression of VEGF and PLGF was decreased. However, the expression of the corresponding receptor, the soluble fms-like tyrosine kinase receptor, which is considered to have anti-angiogenic properties, was elevated in preeclamptic pregnancies. CYR61 and NOV which belong to a group of proteins, the CCN-family, play also an important role in the regulation of placental angiogenesis. Recently, a decreased expression of both proteins in the placentae of preeclamptic women was detected. This review summarizes our current understanding of the role of angiogenic factors in the pathogenesis of preeclampsia.

Defective implantation and placentation: laying the blueprint for pregnancy complications.

Normal implantation and placentation is critical for pregnancy success. Many pregnancy-related complications that present late in gestation (such as pre-eclampsia and preterm labour) appear to have their origins early in pregnancy with abnormalities in implantation and placental development. Implantation is characterized by invasion of the maternal tissues of the uterus by fetal trophoblast, and the degree to which trophoblast invades these tissues appears to be a major determinant of pregnancy outcome. Excessive invasion can lead to abnormally firm attachment of the placenta to the myometrium (placenta accreta) with increased maternal and perinatal morbidity. Inadequate invasion, specifically restricted endovascular invasion, has been implicated in the pathophysiology of such conditions as pre-eclampsia (gestational proteinuric hypertension), preterm premature rupture of membranes, preterm labour, and intrauterine growth restriction. The molecular and cellular mechanisms responsible for implantation remain enigmatic. This review will include an overview of implantation followed by a discussion of a number of molecular mechanisms implicated in defective implantation and placentation including the role of decidual prostaglandins and haemorrhage in regulating trophoblast invasion. An improved understanding of the molecular mechanisms responsible for abnormal implantation and placentation will likely improve clinicians' abilities to treat disorders that occur along this continuum, including infertility, recurrent pregnancy loss, pre-eclampsia, and preterm birth.

Altered expression of angiogenesis-related placental genes in pre-eclampsia associated with intrauterine growth restriction

Aim. The normal endovascular invasion of trophoblast cells and spiral artery remodeling are impaired in pre-eclampsia. Neither the circulating factor secreted by the placenta nor the cause of the widespread endothelial dysfunction in pre-eclampsia has yet been identified. In an attempt to identify novel factors, we performed a gene expression profiling study of placental tissue from women with and without pre-eclampsia.Material and methods. The study group comprised two pre-eclamptic patients with intrauterine growth restriction while the control group comprised three healthy women with uncomplicated pregnancies. Gene expression was studied using Affymetrix Human Genome U133 Plus 2 micro arrays. We focused on genes associated with angiogenesis. Some of the micro array analysis results were verified using real-time reverse transcription polymerase chain reaction (RT-PCR).Results. Gene expression profiling revealed that the expression level of nine genes – ECGF1, JAG1, Palladin, COL18A1, TNFSF12, VEGF, ANPEP, PDGFRA and SERPIN12 – was downregulated whereas the level of four genes – EPAS1, FLT1, SIGLE10 and ANG4 – was upregulated in the study group compared with the control group. The real-time RT-PCR results from JAG1, COL18A1 and FLT1 genes were in accordance with the gene expression results.Conclusion. Our results show new targets for research to understand the mechanisms leading to pre-eclampsia.

Cytotrophoblast induction of arterial apoptosis and lymphangiogenesis in an in vivo model of human placentation

We studied the vascular effects of invasive human cytotrophoblasts in vivo by transplanting placental villi to the fifth mammary fat pads or beneath the kidney capsules of Scid mice. Over 3 weeks, robust cytotrophoblast invasion was observed in both locations. The architecture of the mammary fat pad allowed for detailed analysis of the cells' interactions with resident murine blood vessels, which revealed specific induction of apoptosis in the endothelial cells and smooth muscle walls of the arterioles. This finding, and confirmation of the results in an in vitro coculture model, suggests that a parallel process is important for enabling cytotrophoblast endovascular invasion during human pregnancy. Cytotrophoblast invasion of the kidney parenchyma was accompanied by a robust lymphangiogenic response, while in vitro, the cells stimulated lymphatic endothelial cell migration via the actions of VEGF family members, FGF, and TNF-alpha. Immunolocalization analyses revealed that human pregnancy is associated with lymphangiogenesis in the decidua since lymphatic vessels were not a prominent feature of the nonpregnant endometrium. Thus, the placenta triggers the development of a decidual lymphatic circulation, which we theorize plays an important role in maintaining fluid balance during pregnancy, with possible implications for maternal-fetal immune cell trafficking.

The effect of vascular origin, oxygen, and tumour necrosis factor alpha on trophoblast invasion of maternal arteriesin vitro

Extravillous trophoblasts (EVTs) invade and remodel uterine spiral arteries. Regulatory factors may include inherent vessel susceptibility, local oxygen levels and tumour necrosis factor alpha (TNFalpha). We have used an in vitro model to investigate interstitial and endovascular invasion of myometrial spiral arteries from pregnant and non-pregnant uteri and also omental arteries. To model endovascular invasion, fluorescent-labelled EVTs were perfused into the lumen of these dissected vessels. For interstitial invasion, labelled EVTs were layered on top. Cultures were either maintained in 17% or 3% oxygen, or cultured with TNFalpha. The invasion of arteries from pregnant women occurred via both routes at 17% oxygen, with endovascular invasion more efficient than interstitial. In omental arteries and spiral arteries from non-pregnant women, endovascular invasion was limited. Endovascular and interstitial invasion were lower in all arteries at 3% oxygen. Typically, endovascular events were clustered, with an associated disruption in the adjacent endothelium and smooth muscle. A role for TNFalpha in limiting invasion was also supported. In conclusion, priming of uterine arteries may be necessary prior to EVT invasion. Oxygen is a sensitive regulator within this physiological model and increased invasion at higher pO2 may explain the homing of EVT to maternal arteries rather than veins. Adequate vascular transformation may therefore rely on a balance between vascular receptivity, oxygen partial pressure, and exposure to inflammatory mediators.

Abnormal placentation and the syndrome of preeclampsia

Preeclampsia, particularly the severe cases that occur early in pregnancy, is associated with defects in the (placental) cytotrophoblast differentiation pathway that leads to uterine invasion. At a morphologic level, interstitial invasion often is shallow. Perhaps more significantly, endovascular invasion, particularly the arterial component, is rudimentary. The latter defect is thought to lead to hypoperfusion of the placenta. At a molecular level, these defects are associated with particular deficits in the differentiation process whereby cytotrophoblasts--epithelial cells of ectodermal origin--assume vascular-like properties. Until recently, the question was how the latter defects could lead to the maternal symptoms of this condition. Now a possible link in the form of preeclampsia-associated changes in placental production of vasculogenic/angiogenic substances and their inhibitors has been discovered. It is likely that this new paradigm will improve both diagnosis and treatment of this life-threatening pregnancy complication.

Abnormal placentation and the syndrome of preeclampsia

Preeclampsia, particularly the severe cases that occur early in pregnancy, is associated with defects in the (placental) cytotrophoblast differentiation pathway that leads to uterine invasion. At a morphologic level, interstitial invasion often is shallow. Perhaps more significantly, endovascular invasion, particularly the arterial component, is rudimentary. The latter defect is thought to lead to hypoperfusion of the placenta. At a molecular level, these defects are associated with particular deficits in the differentiation process whereby cytotrophoblasts—epithelial cells of ectodermal origin—assume vascular-like properties. Until recently, the question was how the latter defects could lead to the maternal symptoms of this condition. Now a possible link in the form of preeclampsia-associated changes in placental production of vasculogenic/angiogenic substances and their inhibitors has been discovered. It is likely that this new paradigm will improve both diagnosis and treatment of this life-threatening pregnancy complication.

Vermehrte Expression der induzierbaren NO-Synthase (iNOS) in Makrophagen des Plazentabettes bei schwerer Präeklampsie

Purpose: Impaired invasion of uteroplacental arteries by extravillous trophoblast cells is a key pathogenetic mechanism of preeclampsia. In this context proapoptotic effects (secretion of TNF-α; tryptophan depletion) of macrophages in and around the wall of spiral arteries may play a crucial role. The aim of this study was to assess whether these macrophages in the placental bed of women with severe preeclampsia express NO, which is known to trigger apoptosis in other tissues. Material and Methods: Serial cryostate and paraffin sections were obtained using placental bed biopsies of preeclamptic patients (n=7; spiral arteries n=42) and normotensive healthy controls (n=8; spiral arteries n=57) and immunostained for trophoblast cells, macrophages and iNOs. Results: a) The number of macrophages in the media of spiral arteries (p=0.02) as well as the iNOS expression in these cells (p<0.001) was significantly increased in preeclamptic women compared to normotensive controls. b) Placental bed biopsies of normotensive controls showed significantly less infiltrates of macrophages around the spiral arteries than biopsies obtained from preeclamptic women (p = 0.001). These infiltrates revealed an iNOS expression only in cases of preeclampsia (p < 0.001). Conclusion: Our data suggest that the impaired endovascular invasion of uteroplacental arteries by extravillous trophoblast cells in preeclampsia could be triggered by apoptotic effects via a significantly increased NO synthesis controlled by macrophages in and around the spiral arteries in the placental bed.

Interaction of cocultured decidual endothelial cells and cytotrophoblasts in preeclampsia.

Disturbed cell-cell communication between trophoblasts and the maternal endothelium may be responsible for the deficient endovascular invasion seen in preeclampsia. In vitro studies have been hampered by lack of suitable models to directly examine interactions between these cell types. Using a bilayer coculture model, we examined the effect of decidual endothelial cells on matrix metalloproteinase secretion and the migration of cytotrophoblasts from preeclamptic pregnancies. Cells were incubated on semipermeable membranes in 20% or 2% O(2) with or without the tumor promoter phorbol 12-myristate 13-acetate, which activates matrix metalloproteinase-2 and -9 in endothelial cells. Cytotrophoblasts from preeclamptic pregnancies secreted significantly less matrix metalloproteinase-2 and -9 than their normal counterparts. Although decidual endothelial cells downregulated cytotrophoblast migration in normal pregnancy, this was not observed in cocultures with cytotrophoblasts from preeclamptic pregnancies. In addition, cytotrophoblasts from preeclamptic pregnancies altered phorbol myristate acetate-induced activation of endothelial matrix metalloproteinases. Hypoxia increased cytotrophoblast migration when cells were incubated alone but not in coculture with decidual endothelial cells due to increased adhesion between the two cell types. These results suggest dysfunctional interactive regulation of migration and matrix metalloproteinase secretion in preeclampsia that could result in abnormal endovascular trophoblast invasion of the maternal vasculature.

Hypothesis: selective phosphodiesterase-5 inhibition improves outcome in preeclampsia

The pathogenesis of preeclampsia stems from aberrant changes at the placental interface. The trophoblastic endovascular invasion of tonic spiral arteries that converts them to passive conduits falters. Uteroplacental insufficiency and fetoplacental hypoxemia result. Secondary maternal oxidative stress and an excessive inflammatory response to pregnancy generate the clinical syndrome of preeclampsia. Current treatment focuses on preventing seizures, controlling hypertension, preserving renal function and delivering the baby. We propose that the pathophysiological changes induced by preeclampsia in the placenta parallel those caused by persistent hypoxemia in the lungs at high altitude or with chronic obstructive pulmonary disease. Unrelenting pulmonary hypoxic vasoconstriction induces pulmonary hypertension and cor pulmonale. Inhalation of nitric oxide and phosphodiesterase-5 inhibitors opposes pulmonary hypoxic vasoconstriction, alleviates pulmonary hypertension and improves systemic oxygenation. Notably nitric oxide donor therapy also counters hypoxemic fetoplacental vasoconstriction, a biological response analogous to pulmonary hypoxic vasoconstriction. Fetal oxygenation and nutrition improve. Placental upstream resistance to umbilical arterial blood flow decreases. Fetal right ventricular impedance falls. Heart failure (cor placentale) is avoided. Emergency preterm delivery can be postponed. Other than low dose aspirin and antioxidants vitamins C and E no available therapy specifically targets the underlying disease profile. We hypothesize that, like nitric oxide donation, pharmacological inhibition of placental phosphodiesterase-5 will also protect the fetus but for a longer time. Biological availability of guanosine 3 ′5 ′-cyclic monophosphate is boosted due to slowed hydrolysis. Adenosine 3 ′5 ′-cyclic monphosphate levels increase in parallel. Cyclic nucleotide accumulation dilates intact tonic spiral arteries and counters hypoxemic fetoplacental vasoconstriction. Intervillous and intravillous perfusion pick up. Maternal to fetal placental circulatory matching improves. Enhanced placental oxygen uptake alleviates hypoxemic fetal stress. Appropriate fetal nutrition resumes. Cor placentale and severe intrauterine growth restriction are averted. Increased maternal cyclic nucleotide concentrations promote systemic vasodilatation so that blood pressures fall. Preemption of oxidative stress initiated by “consumptive” oxidation of nitric oxide stabilizes the vascular endothelium and corrects coagulopathy. Anti-inflammatory and immunosuppressant adenosine 3 ′5 ′-cyclic monphosphate offsets the extreme gestational inflammatory response. Cellular injury and multi-organ damage are prevented. One tablet a day of the new long acting phosphodiesterase-5 inhibitor, tadalafil (half life of 17.5 h) theoretically should allow a preterm pregnancy affected by preeclampsia to continue safely. Selective monitoring of vital organ functions guards against life-threatening maternal complications. Regular biophysical profiling warns the obstetrician of impending fetal compromise. Fetal growth and vital organ maturation can continue. As a result workloads imposed upon neonatal intensivists will lighten. Parental anxiety and concern will be allayed. The cost of treating preeclamptic mothers and their extremely low birth weight infants will decrease. Money saved by midwifery services in poorer states can be used to pay for better prenatal care. Severe preeclampsia/eclampsia will be less common. Maternal and perinatal morbidity and mortality will be reduced. Because the human immunodeficiency virus often infects individuals at a workforce eligible age, the global acquired immunodeficiency syndrome pandemic has already brought many nations to the brink of economic ruin. Potentially productive lives saved for the future will help restore them fiscally.

CXCL12 expression by invasive trophoblasts induces the specific migration of CD16– human natural killer cells

AbstractIn the maternal decidua, natural killer (NK) cells, characterized by lack of CD16, are found in direct contact with the fetal extravillous trophoblasts (EVTs). It is yet unknown which factors contribute to the specific homing of this unique NK subset to the decidua. In this study we analyze the chemokine receptor repertoire on various NK populations derived from the peripheral blood and decidua. We show that CXCR4 and CXCR3 receptors are preferentially expressed on CD16– NK subsets derived either from the peripheral blood or the decidua and that these receptors are involved in migration of all NK subsets to their ligands. We further demonstrate in vivo that invading EVTs that eventually perform endovascular invasion express CXCL12, the ligand for CXCR4, but not ligands for CXCR3. Indeed, specific accumulation of the CD16– NK cells at the expense of CD16+ cells was observed only when in vitro migration was performed with ligands for CXCR4. Finally, incubation of the peripheral blood CD16– NK cells with cytokines present in the decidua, especially interleukin 15 (IL-15), resulted in the expression of chemokine receptor repertoire similar to that observed on decidual NK cells, suggesting an additional important regulatory effect of local decidual cytokines.

Gestation stage-dependent intrauterine trophoblast cell invasion in the rat and mouse: novel endocrine phenotype and regulation

Trophoblast cell invasion into the uterine wall is characteristic of hemochorial placentation. In this report, we examine trophoblast cell invasion in the rat and mouse, the endocrine phenotype of invasive trophoblast cells, and aspects of the regulation of trophoblast cell invasion. In the rat, trophoblast cells exhibit extensive interstitial and endovascular invasion. Trophoblast cells penetrate through the decidua and well into the metrial gland, where they form intimate associations with the vasculature. Trophoblast cell invasion in the mouse is primarily interstitial and is restricted to the mesometrial decidua. Both interstitial and endovascular rat trophoblast cells synthesize a unique set of prolactin (PRL)-like hormones/cytokines, PRL-like protein-A (PLP-A), PLP-L, and PLP-M. Invading mouse trophoblast cells also possess endocrine activities, including the expression of PLP-M and PLP-N. The trafficking of natural killer (NK) cells and trophoblast cells within the mesometrial uterus is reciprocal in both the rat and mouse. As NK cells disappear from the mesometrial compartment, a subpopulation of trophoblast cells exit the chorioallantoic placenta and enter the decidua. Furthermore, the onset of interstitial trophoblast cell invasion is accelerated in mice with a genetic deficiency of NK cells, Tgε26 mice, implicating a possible regulatory role of NK cells in trophoblast cell invasion. Additionally, the NK cell product, interferon-γ (IFNγ), inhibits trophoblast cell outgrowth, and trophoblast cell invasion is accelerated in mice with a genetic deficiency in the IFNγ or the IFNγ receptor. In summary, trophoblast cells invade the uterine wall during the last week of gestation in the rat and mouse and possess a unique endocrine phenotype, and factors present in the uterine mesometrial compartment modulate their invasive behavior.