Bed Biopsies Research Articles

Nuclear Localisation of the Endocannabinoid Metabolizing Enzyme Fatty Acid Amide Hydrolase (FAAH) in Invasive Trophoblasts and an Association with Recurrent Miscarriage

Endocannabiniods are lipid signalling molecules that are related to the major psychoactive component in marijuana, delta-9-tetrahydrocannabinol and are increasingly recognized as being important in implantation and development of early embryos. The endocannabinoid anandamide, is metabolized by the enzyme fatty acid amide hydrolase (FAAH), and insufficient levels of this enzyme have been implicated in spontaneous miscarriage in women and implantation failure in mice. We screened placental bed biopsies and placental tissue from 45 women with recurrent miscarriage and 17 gestation-matched women with normal pregnancies for the expression of FAAH by immunohistochemistry. Unexpectedly, the enzyme appeared to be localised to the nucleus of trophoblasts and this was confirmed by western blotting of sub-cellular fractions and confocal microscopy. FAAH was expressed in the cytoplasm of large decidual stromal cells and significantly more women with recurrent miscarriage (73%) expressed FAAH in these cells than women with normal pregnancy (31%). FAAH was also expressed in the nucleus of extravillous trophoblasts that had invaded the decidua from 67% of women with recurrent miscarriage but was not expressed by these cells in any women with normal pregnancies. In contrast, FAAH was expressed in extravillous trophoblasts that had migrated out of the villi but that had not yet invaded the decidua in both normal pregnancies and in cases of recurrent miscarriage. FAAH was also present in the nucleus of a small number of villous trophoblasts in some specimens. FAAH appears to be over expressed in trophoblasts that have invaded the decidua, as well as in large decidual stromal cells in many cases of recurrent miscarriage. This may reflect inadequate control of the cannabinoid system in the uterus of women who experience recurrent miscarriages. The functional significance of the unexpected nuclear localisation of FAAH in trophoblasts is not yet clear.

Expression of Extracellular Signal-Regulated Kinase1/2 and p38 Mitogen-Activated Protein Kinase in the Invasive Trophoblasts at the Human Placental Bed

Background Mitogen-activated protein kinases (MAP kinases) participate in signal transduction pathways that control embryogenesis, cell differentiation, cell proliferation and cell death. The roles of extracellular signal-regulated kinase1/2 (ERK1/2) and p38 MAP kinase in the differentiation and invasion of human trophoblasts have been studied. However, the in vivo expression and activation of ERK1/2 and p38 at the placental bed have not been elucidated. Methods The study group consisted of placental bed biopsy tissues obtained from the pregnancies without preeclampsia ( n = 24) and with preeclampsia ( n = 8) between 31 and 40 weeks of gestation. We evaluated the expressions and phosphorylations of ERK1/2 and p38 MAP kinase in the invasive trophoblasts in the placental bed tissues using immunohistochemistry. Results p38 and phospho-p38 MAP kinase were not detected in invasive trophoblasts in cases or controls. ERK1/2 and phospho-ERK1/2 were positive in invasive trophoblasts albeit with variable staining. Phosphorylation of ERK1/2 was significantly less frequent in invasive trophoblasts in placental bed biopsies from women with preeclampsia compared with normotensive controls. Conclusion These findings suggest that preeclampsia is associated with decreased activation of ERK1/2 in invasive trophoblasts in vivo.

Nail Changes in Langerhans Cell Histiocytosis: A Possible Marker of Multisystem Disease

We describe a child with a 6-month history of onycholysis, subungual hyperkeratosis, and hemorrhages in most of her fingernails and toenails. Nail involvement preceded the identification of osteolytic lesions at the mastoid on a cranial computed tomography scan, which was performed because of repeated episodes of acute otitis media. Some weeks later, a small number of erythematous papules developed over the trunk and face. The diagnosis of Langerhans cell histiocytosis was made by histopathologic examination of bone, skin, and bed and matrix nail biopsies. Response to treatment with vinblastine and prednisone was excellent. Nail changes in Langerhans cell histiocytosis are extremely uncommon, particularly as the presenting manifestation of the disease. The role of nail involvement as an unfavorable prognostic sign is unclear.

Pre‐eclampsia is associated with dendritic cell recruitment into the uterine decidua

Pre-eclampsia is a leading cause of fetal and maternal morbidity and mortality that preferentially affects primiparous patients. It is associated with systemic inflammation and impaired trophoblast invasion of the decidua. Decidual cells are the major cell type of the pregnant endometrium. Macrophages and dendritic cells are major specialized antigen-presenting cells that promote both innate immunity and immune tolerance. Macrophage infiltration is implicated in impaired trophoblast invasion that leads to pre-eclampsia. By contrast, the potential modulating role of decidual dendritic cells in the genesis of pre-eclampsia has not been investigated. Interleukin-1beta (IL-1beta), a pro-inflammatory cytokine, has been implicated in the genesis of pre-eclampsia. Thus, we postulate that pre-eclampsia would be associated with enhanced decidual dendritic cells infiltration and that IL-1beta would enhance the production of relevant dendritic cell-recruiting chemokines. We used immunohistochemistry to demonstrate a marked infiltrate of immature and mature dendritic cells in pre-eclamptic decidua. Further, immunohistochemistry and immunoassays of placental bed biopsies revealed that pre-eclamptic decidua displays elevated levels of several monocyte- and dendritic cell-recruiting chemokines. Leukocyte-free first-trimester decidual cells were then treated with IL-1beta, which enhanced the mRNA and protein expression of these chemokines. The current study also confirmed previous reports that macrophages directly impaired trophoblast invasion and that this inhibitory effect is augmented by the conditioned medium of IL-1beta-treated first-trimester decidual cells. However, unlike macrophages, dendritic cells did not directly impede trophoblast invasion. This study demonstrates that the inflammatory milieu of pre-eclampsia induces decidual cells to promote dendritic cell infiltration. Given their unusual versatility in mediating both immunity and tolerance, these novel findings suggest that dendritic cells may play a critical role either in the pathogenesis of pre-eclampsia or its prevention in subsequent pregnancies.

Homeodomain protein HLX is expressed primarily in cytotrophoblast cell types in the early pregnancy human placenta

Homeobox genes are a large family of transcription factors. Of these, the HLX homeobox gene (previously known as HLX1 and HB24) is important for normal placentation. We have previously shown that HLX mRNA expression is significantly reduced in fetal growth-restricted human placentae compared with control placentae. In this study, a rabbit polyclonal antibody to the homeodomain protein HLX was raised and characterised. Western analysis revealed a protein of 50 kDa. HLX protein was detected in cellular nuclei in the cytotrophoblast-derived cell lines HTR8/SVneo, SGHPL-4, JEG-3, JAR and BeWo. Dual labelling with cytokeratin 7 was used to determine the spatial distribution of HLX in the early placenta and fetal membranes, showing both a perinuclear and punctate nuclear distribution for HLX. In the early pregnancy placenta HLX was localised to villous cytotrophoblast, and extravillous cytotrophoblast nuclei in the proximal regions of the cytotrophoblast cell columns, but was not detected at significant levels in the syncytiotrophoblast. In first trimester placental bed biopsies, HLX expression was not localised to the nucleus but instead was found in the cytoplasm. We conclude that HLX is primarily expressed in cytotrophoblast cell types in the human placenta and propose that HLX is involved in cytotrophoblast proliferation and downregulation of cell differentiation.

Placental expression profiling in preeclampsia: local overproduction of hemoglobin may drive pathological changes

To create a library enriched in cDNAs from preeclamptic placentas to print onto microarrays for placental profiling of preeclampsia (PE) and high risk pregnancies. Prospective study. University women's clinic and academic research laboratory. Ten patients with PE, 5 with PE and bilateral notching, 5 with bilateral notching without PE, and 15 normotensive patients were recruited. Placenta and placenta bed biopsies were collected after delivery. Subtracted libraries of PE transcripts were produced, and cDNAs from these libraries were used to make PE-specific cDNA arrays. Results were verified quantitatively using real-time polymerase chain reaction (PCR) and histologically using in situ hybridization and immunohistochemistry. Thirty genes were significantly altered in at least one group comparison. Differences in two candidate genes were confirmed using quantitative real-time PCR. Hemoglobin alpha2 and gamma transcripts were significantly overexpressed in the PE placenta. Scattered cells in the placenta and placental blood vessels were shown to express genes encoding these hemoglobin chains. We demonstrate increased hemoglobin production in the PE placenta. The hemoglobin may be released into the placenta blood vessel lumen. Free heme and hemoglobin are potent toxins that cause endothelial damage and inflammation.

Delayed and Deficient Dermal Maturation in Mice Lacking the CXCR3 ELR-Negative CXC Chemokine Receptor

Replacement of wounded skin requires the initially florid cellular response to abate and even regress as the dermal layer returns to a relatively paucicellular state. The signals that direct this "stop and return" process have yet to be deciphered. CXCR3 chemokine receptor and its ligand CXCL11/IP-9/I-TAC are expressed by basal keratinocytes and CXCL10/IP-10 by keratinocytes and endothelial cells during wound healing in mice and humans. In vitro, these ligands limit motility in dermal fibroblasts and endothelial cells. To examine whether this signaling pathway contributes to wound healing in vivo, full-thickness excisional wounds were created on CXCR3 wild-type (+/+) or knockout (-/-) mice. Even at 90 days, long after wound closure, wounds in the CXCR3(-/-) mice remained hypercellular and presented immature matrix components. The CXCR3(-/-) mice also presented poor remodeling and reorganization of collagen, which resulted in a weakened healed dermis. This in vivo model substantiates our in vitro findings that CXCR3 signaling is necessary for inhibition of fibroblast and endothelial cell migration and subsequent redifferentiation of the fibroblasts to a contractile state. These studies establish a pathophysiologic role for CXCR3 and its ligand during wound repair.

Expression of TGF beta in the placental bed is not altered in sporadic miscarriage

Extravillous trophoblast invasion of uterine stroma and spiral arteries (SA) is essential for normal pregnancy and is reduced in preeclampsia and late miscarriage. The control mechanisms are not understood, but transforming growth factor-beta (TGF-β) may be a candidate. Placental and placental bed biopsies were obtained from early (8 +0–12 +6 weeks) euploid miscarriages ( n = 10), early aneuploid miscarriages ( n = 10), late (13 +0–19 +6 weeks) euploid miscarriages ( n = 10) and controls of the same gestation ( n = 20). Frozen sections were immunostained for TGF-β1, 2 and 3. Immunoreactivity of trophoblast and uterine cell populations was assessed semi-quantitatively. TGF-β1 immunolocalization was limited to extracellular matrix in cytotrophoblast islands and cytotrophoblast shell, perivascular fibrinoid and interstitial trophoblast and did not differ in miscarriage compared with controls. TGF-β2 was expressed additionally in endovascular trophoblast and multinucleate trophoblast giant cells. There was no aberrant TGF-β2 immunolocalization in late miscarriage, but TGF-β2 immunoreactivity was increased in extracellular matrix in cytotrophoblast islands in early miscarriage. TGF-β3 was absent from all cell populations. Stromal and extravillous trophoblast TGF-β2 immunolocalization suggests a more important role in trophoblast invasion than TGF-β1, but neither isoform was altered in miscarriage. Altered TGF-β localization is therefore unlikely to play a role in abnormal trophoblast invasion and SA transformation in miscarriage.

Proportion of peripheral blood and decidual CD4+ CD25bright regulatory T cells in pre-eclampsia

CD4(+) CD25(bright) regulatory T (T(reg)) cells have been identified as a principle regulator of tolerance during pregnancy. In the setting of pre-eclampsia, however, little is known about the dynamics of these cells. In the current study, we determined CD4(+) CD25(bright) T(reg) cells in the peripheral blood using flow cytometry and forkhead box P3 (FoxP3(+)) cells at the placental bed using immunohistochemical staining. Peripheral blood mononuclear cells (PBMC) of 38 pre-eclamptic cases (17 cases Japanese, 21 cases Polish), 40 normal late pregnancy subjects (20 subjects Japanese, 20 subjects Polish), and 21 non-pregnant healthy controls (10 subjects Japanese, 11 subjects Polish) were included. We found the percentage of CD25(bright) cells within the CD4(+) T cell population in PBMC was reduced significantly in both Japanese and Polish pre-eclamptic cases than in normal pregnancy subjects (P < 0.001) and non-pregnant healthy controls (P < 0.001). Also, the percentage of FoxP3(+) cells within CD3(+) T cells in the placental bed biopsy samples of pre-eclamptic cases were decreased compared to those in normal pregnancy subjects. These findings suggest that a decreased number of T(reg) cells was present in pre-eclampsia, and these changes might break the maternal tolerance to the fetus.

Distribution of CD14+ and CD68+ Macrophages in the Placental Bed and Basal Plate of Women With Preeclampsia and Preterm Labor

Objective Macrophages play a key role in implantation, placentation and parturition. Yet, whether or not the number of macrophages at the fetomaternal interface (basal plate of the placenta and placental bed) is altered in women with preeclampsia is the subject of controversy. The purpose of this study was to compare the immunoreactivity and distribution patterns of CD14 and CD68 positive macrophages in both the basal plate and placental bed from preeclamptic and non-preeclamptic pregnancies. Methods A cross-sectional study was conducted. Paraffin embedded sections of placental tissues and placental bed biopsies were obtained from patients with early onset preeclampsia ( n = 10) and from those with preterm labor/delivery ( n = 10) without preeclampsia matched for gestational age. Double immunohistochemistry using antibodies to CD14 and CD68 was performed, and the density of double or single positive cells in the basal plate and placental bed was evaluated. Non-parametric statistics were used for analysis. Results 1) A unique subset of CD14−/CD68+ cells was identified. The cells in question were present at a higher level in the decidua than in the myometrial segment of the placental bed ( p < 0.01); 2) The density and proportion of CD14+/CD68+ cells (double positive cells) were significantly higher in the myometrial segment than in the basal plate ( p = 0.0003); and 3) There were no significant differences in the density and patterns of immunopositive macrophages in the basal plate, the decidua, and the myometrium between women with preeclampsia and those with preterm labor/delivery ( p > 0.05). Conclusion The macrophages at the fetomaternal interface can be dichotomized by CD14 and CD68 immunoreactivity. A gradient of CD14+/CD68+ macrophages was demonstrated between the superficial myometrium and the basal plate regardless of the etiology of preterm birth (preeclampsia or spontaneous preterm labor). The biological function of single positive (CD14−/CD68+) and double positive (CD14+/CD68+) macrophages at the fetomaternal interface remains to be established. The overall findings also suggest that the discrepancies in the literature are due to the varying markers used to detect macrophages and in the anatomical plane of the fetomaternal junction analyzed.

Multiple calcified subungual epidermoid inclusions

Subungual epidermoid inclusions (also known as subungual onycholemmal cysts) are an uncommon and distinctive nail abnormality occurring in the dermis of the nail bed. Clinically the nail plate may exhibit onychodystrophy, clubbing, ridging, thickening, pigmentation, or appear normal. We report the case of a patient with onychodystrophy of the right halux of 7 years' duration. This case is presented with serial pictures demonstrating the gradual development of nail plate thickening, yellow discoloration, and nail bed hyperkeratosis indicative of the disease. She had negative fungal cultures, poor response to topical and oral antifungal agents, and an initial nondiagnostic superficial biopsy. Repeat full-thickness nail bed biopsy results revealed multiple calcified subungual epidermoid inclusions epidermoid inclusions. Histologic features included characteristic elongation of the rete ridges with cyst formation and pinching off of the connection to the nail bed epithelium, forming free-lying cysts within the dermis of the nail bed. The cysts contained compact onycholemmal keratin and calcification. A granular layer was not present. This case reinforces the need to clinically reassess, possibly x-ray, and perform a sufficient biopsy for persistent undiagnosed nail unit disorders. Subungual calcified inclusions may be an underrecognized and more common entity than currently recognized.

Fetal macrophages are not present in the myometrium of women with labor at term

The basic mechanisms responsible for human parturition remain to be elucidated. The influx of fetal leukocytes into the myometrium has been recently proposed to be a crucial event in the onset of murine parturition. Surfactant protein-A has been implicated in the initiation of labor. In mice, it is thought that surfactant protein-A induces migration and subsequent activation of amniotic fluid macrophages of fetal origin, which then invades the myometrium. The present study was conducted to determine whether fetal macrophages invade the myometrium of women in labor. Placental bed biopsy specimens were obtained from patients in labor who delivered male neonates at term (n = 7). Myometrial sections of postpartum hysterectomy specimens obtained from women who delivered of male neonates (n = 3) were also analyzed. Formalin-fixed, paraffin-embedded sections were immunostained for CD68 or CD14 (which are markers for macrophages); immunoreactive myometrial macrophages were specifically procured by laser capture microdissection. Sex typing was done by polymerase chain reaction for the amelogenin gene with genomic DNA that was isolated from the macrophages. Chromogenic in situ hybridization with a Y chromosome-specific probe was also performed on paraffin-embedded histologic sections. Amelogenin allelotypes of the macrophages were consistent with female alleles in all cases that were tested, indicating a maternal origin. Chromogenic in situ hybridization demonstrated the absence of Y chromosome-positive mononuclear cells in the myometrium in all cases. These observations, from a limited number of cases, suggest that migration of fetal macrophages from the amniotic cavity or the chorioamniotic membranes into the myometrium does not occur during human labor. The trafficking of fetal macrophages in labor seems to be different in humans and mice.

Mechanisms regulating cytotrophoblast invasion in normal pregnancy and pre‐eclampsia

The placental bed underlies the placenta and includes the decidua basalis and underlying myometrium containing the uterine spiral arteries. For successful human haemochorial placentation, the placental bed spiral arteries must undergo considerable alterations. These physiological modifications are thought to be brought about by the interaction of invasive cytotrophoblast with the spiral artery vessel wall. Failure of spiral artery transformation is thought to play an important role in the sequence of events that gives rise to pre-eclampsia. The mechanisms that control human trophoblast invasion in normal, let alone abnormal pregnancy, are still poorly understood. Much of the information on the early physiological changes within the placental bed comes from studies on intact hysterectomy specimens.(1) Details of such events in late pregnancy and in pregnancies complicated by pre-eclampsia and fetal growth restriction are principally derived from the study of placental bed biopsies taken at Caesarean section. The methods of sampling the placental bed have been reviewed elsewhere.(2) Many investigators have relied on in vitro models of trophoblast invasion. In vitro models can be extremely useful in dissecting out some of these processes but may be open to artefacts. The mechanisms underlying normal and failed trophoblast invasion appear to be complex. In this manuscript the mechanisms that control the invasion of trophoblast into the decidua and myometrium are reviewed. Along with this is a review of the purported mechanisms underlying failed spiral artery transformation. Particular emphasis has been placed on topics that have been best studied.

Late sporadic miscarriage is associated with abnormalities in spiral artery transformation and trophoblast invasion

Trophoblast invasion of uterine decidua and myometrium, and spiral artery transformation, are essential for the development of normal pregnancy; this process is impaired in pre-eclampsia, fetal growth restriction, and pre-term labour. The hypothesis that late miscarriage is associated with reduced trophoblast invasion and spiral artery transformation was tested in a large series of placental bed biopsies containing decidua and myometrium from late, karyotyped, embryonic miscarriage (>or=13 weeks' gestation; n = 26; n = 96 spiral arteries) and gestationally matched ultrasound-dated normal pregnancies (n = 74; n = 236 spiral arteries). Cryostat sections were immunostained using an avidin-biotin peroxidase technique for cytokeratin, desmin, and von Willebrand factor to detect trophoblast, myometrium, and vascular smooth muscle and endothelium, respectively. Trophoblast invasion and individual features of spiral artery transformation were assessed and analysed using a logistic regression model. Compared with normal pregnancy, myometrial spiral arteries in late miscarriage showed reduced endovascular (4% vs. 31%, p = 0.001) and intramural trophoblast (76% vs. 88%, p = 0.05), and less extensive fibrinoid change (4% vs. 18%, p = 0.01). In contrast, endovascular trophoblast in decidual spiral arteries was increased (40% vs. 66%, p = 0.04). These findings suggest that, in common with pre-eclampsia, late sporadic miscarriage may be associated with reduced trophoblast invasion and inadequate transformation of myometrial spiral arteries.

Early embryonic demise: no evidence of abnormal spiral artery transformation or trophoblast invasion

Invasion by extravillous trophoblast of uterine decidua and myometrium and the associated spiral artery 'transformation' are essential for the development of normal pregnancy. Small pilot studies of placental bed and basal plate tissues from miscarriages have suggested that impaired interstitial and endovascular trophoblast invasion may play a role in the pathogenesis of miscarriage. The hypothesis that early miscarriage is associated with reduced extravillous trophoblast invasion and spiral artery transformation was tested in a large series of placental bed biopsies containing decidua and myometrium and at least one spiral artery from early, karyotyped embryonic miscarriages (<or=12 weeks' gestation; n = 50) dated from the last menstrual period and ultrasound scan dated normal pregnancies (n = 78). Frozen sections were immunostained to demonstrate trophoblast (cytokeratin), myometrium and spiral artery medial smooth muscle (desmin), and endothelium (von Willebrand factor). Trophoblast invasion and individual features of spiral artery transformation were assessed histologically in spiral arteries of miscarriages (n = 176) and controls (n = 246) and analysed statistically using a logistic regression model. Trophoblast invasion of uterine tissues and spiral artery transformation did not differ between euploid and aneuploid early miscarriage and also did not differ significantly from normal pregnancy. These findings suggest that failed trophoblast invasion and spiral artery transformation do not have a pivotal role in the pathogenesis of early miscarriage.

Placental apoptosis and adhesion molecules expression in the placenta and the maternal placental bed of pregnancies complicated by fetal growth restriction with and without pre-eclampsia

SummaryThe aim of the study was to examine the expression of adhesion molecules VCAM-1 and ICAM-3 in placental tissue samples and placental bed (maternal decidual tissue) biopsies of pregnancies complicated by pre-eclampsia (PE) and fetal growth restriction (FGR), and to determine whether PE and FGR are associated with an increase in placental apoptosis. We studied placentas and placental bed samples of 49 third trimester pregnancies complicated by FGR (26 with associated PE, 23 without PE) and 25 normotensive healthy pregnant women. Placental apoptosis was assessed by the TUNEL method. Immunohistochemistry was used to assess expression of the VCAM-1 and ICAM-3. There was no significant difference in the staining intensity of VCAM-1 in placentas ( p = 0.472) and placental bed biopsies ( p = 0.754) of women delivering appropriate for gestational age and growth restricted fetuses (with and without associated PE). The amount of lymphocytes staining positively with ICAM-3 was significantly higher in both placental and placental bed biopsies of women delivering growth restricted fetuses compared with control pregnancies ( p < 0.001). Fetal growth restricted pregnancies with associated PE showed higher staining of ICAM-3 in placental compared with placental bed samples ( p = 0.049). In fetal growth restricted placentas, apoptotic nuclei were more abundant compared with control placentas ( p < 0.001). Increased expression of ICAM-3 on lymphocyte surface of both maternal and fetal side, suggests lymphocyte overactivation in PE and FGR. Increased placental apoptosis may play an important role in the pathogenesis or sequelae of PE.

Microvessel density in the placental bed among preeclampsia patients

Morphological changes in the spiral arteries of the placental bed have been studied in patients with preeclampsia, one of the largest causes of maternal and perinatal morbidity and mortality. The reports show that vasospasm and vascular endothelial injury were two major pathological conditions for preeclampsia. The aim of this study was to investigate the microvessel density of spiral arteries in the placental bed, in pregnancies complicated by hypertension and proteinuria, and in normal pregnancies. This was a cross-sectional survey of immunohistochemical studies on biopsies from the spiral arteries of the placental bed, among women undergoing cesarean sections for clinical and obstetrical reasons at Universidade Federal de São Paulo, São Paulo, Brazil. Placental bed biopsies were obtained during cesarean section after placenta removal, with direct viewing of the central area of placenta insertion. The microvessel density of spiral arteries was measured by immunohistochemical methods in decidual and myometrial segments, using CD34 antibody. Biopsies containing spiral arteries were obtained from 34 hypertensive pregnant women with proteinuria, and 26 normotensive pregnant women. The microvessel densities in decidual and myometrial segments of the placental bed were compared between the groups. It was observed that, with increasing blood pressure and proteinuria, the microvessel density gradually decreased. The presence of high levels of hypertension and proteinuria may be associated with a progressive decrease in microvessel density in the placental bed.

Altered protease expression by periarterial trophoblast cells in severe early-onset preeclampsia with IUGR

Adaptation of uteroplacental arteries in patients with early-onset preeclampsia combined with IUGR is compromised due to insufficient invasion of extravillous trophoblast cells (EVT) into the spiral artery wall. The underlying molecular mechanisms are widely unknown. We investigated expression and possible mechanisms of regulation of different matrix-metalloproteases (MMPs) by EVT in placental bed biopsies from patients with early onset preeclampsia combined with IUGR and healthy pregnant women. Expression of MMP-3 and MMP-7 by EVT was markedly reduced in preeclamptic patients, especially close to spiral arteries. In contrast to healthy pregnancies these cells strongly expressed the receptor for leukemia inhibitory factor (LIF). LIF is known to suppress MMP-expression and is produced by uterine natural killer (uNK) cells which we found to be present in higher concentrations in the placental bed of preeclamptic patients, and accumulating aside the spiral arteries. We speculate that in preeclampsia a maternal immune cell network accumulating and interfering in the placental bed leads to an altered cytokine environment, resulting in disturbed trophoblast cell function such as impaired MMP expression and reduced invasiveness.

Normal and abnormal transformation of the spiral arteries during pregnancy

This article reviews the anatomy and physiology of the uterine circulation, with emphasis on the remodeling of spiral arteries during normal pregnancy, and the timing and anatomical pathways of trophoblast invasion of the spiral arteries. We review the definitions of the placental bed and basal plate of the placenta, their relevance to the study of the physiologic transformation of the spiral arteries, as well as the methods to obtain and examine placental bed biopsy specimens. We also examine the role of the extravillous trophoblast in normal and abnormal pregnancies, and the criteria used to diagnose failure of physiologic transformation of the spiral arteries. Finally, we comment on the use of uterine artery Doppler velocimetry as a surrogate marker of chronic uteroplacental ischemia.

Morphometry of the Basal Plate Superficial Uteroplacental Vasculature in Normal Midtrimester and at Term

Uteroplacental (UP) vascular arterial pathology has been associated with pregnancy complications. UP arterial structure has been characterized in placental bed biopsies, at the decidual-myometrial junction. Basal plate UP arteries, which are delivered with the placenta and thus routinely available, are not well characterized. We compared basal plate UP arterial segment morphometry in cases of elective termination of a clinically normal pregnancy at 11 to 24 weeks and of term birth. This study was done in a community-based obstetric service in New York City. UP arteries were identified in placentas of 20 midtrimester (MT) cases and 17 term (TERM) cases. We measured 336 UP artery cross-sections from 46 TERM and 290 MT cases. The basal plate UP artery path length was calculated as the distance between (x,y) coordinates of estimated centers of lumen cross-sections. Basal plate thickness near UP arteries, UP artery cross-sectional areas, vascular luminal eccentricity, and radial standard deviation were directly measured off digital images. Nonparametric and parametric methods compared groups, with P < 0.05 considered statistically significant. In TERM cases, the basal plate thickness near UP arteries was 1.8-fold thinner (P = 0.002) and mean basal plate path lengths were 2.13-fold shorter (P < 0.0001) than in MT cases. Mean TERM UP artery cross-sectional area was 3.15-fold larger, the major axis was 1.95-fold larger, and the minor axis was 1.75-fold larger than in MT arteries (P = 0.001 to 0.008). Our data demonstrate that basal plate UP arteries (delivered with the placenta) are less tortuous, with shorter path lengths and larger areas as gestation advances. Normative morphometric data may allow improved diagnostics of placentas from complicated pregnancies.