Placental Angiogenesis Research Articles

Bisphenol A affects placental layers morphology and angiogenesis during early pregnancy phase in mice.

Bisphenol A (BPA) is a widespread endocrine disrupter mainly used in food contact plastics. Much evidence supports the adverse effects of BPA, particularly on susceptible groups such as pregnant women. The present study considered placental development - relevant for pregnancy outcomes and fetal nutrition/programming - as a potential target of BPA. Pregnant CD-1 mice were administered per os with vehicle, 0.5 (BPA05) or 50 mg kg(-1) (BPA50) body weight day(-1) of BPA, from gestational day (GD) 1 to GD11. At GD12, BPA50 induced significant degeneration and necrosis of giant cells, increased vacuolization in the junctional zone in the absence of glycogen accumulation and reduction of the spongiotrophoblast layer. In addition, BPA05 induced glycogen depletion as well as significant nuclear accumulation of β-catenin in trophoblasts of labyrinthine and spongiotrophoblast layers, supporting the activation of the Wnt/β-catenin pathway. Transcriptomic analysis indicated that BPA05 promoted and BPA50 inhibited blood vessel development and branching; morphologically, maternal vessels were narrower in BPA05 placentas, whereas embryonic and maternal vessels were irregularly dilated in the labyrinth of BPA50 placentas. Quantitative polymerase chain reaction evidenced an estrogen receptor β induction by BPA50, which did not correspond to downstream genes activation; indeed, the transcription factor binding sites analysis supported the AhR/Arnt complex as regulator of BPA50-modulated genes. Conversely, Creb appeared as the main transcription factor regulating BPA05-modulated genes. Embryonic structures (head, forelimb) showed divergent perturbations upon BPA05 or BPA50 exposure, potentially related to unbalanced embryonic nutrition and/or to modulation of genes involved in embryo development. Our findings support placenta as an important target of BPA, even at environmentally relevant dose levels.

The role of microRNAs on angiogenesis and vascular pressure in preeclampsia: The evidence from systematic review

BackgroundIn pre-clinical stage of preeclampsia, placental angiogenesis is impaired leading to hypoxic placenta and dysregulation of pro- and anti-angiogenetic factors. As a consequence, these cause elevated systemic vascular resistance, vasoconstriction and hypertension in clinical stage of preeclampsia. Dysregulation of microRNAs (miRNAs) has been observed among preeclampsia patients and they are involved in several aspects of preeclampsia pathogenesis. AimsTo evaluate the roles of miRNAs in angiogenesis and vascular pressure in preeclampsia. Material and methodsArticles from MEDLINE database (between 2007 and February 2015) were searched by using the combination of Medical Subject Headings (MeSH terms) “preeclampsia”, “pre-eclampsia”, “miRNA” and “microRNA”. All sources of miRNAs, all types of preeclampsia and all techniques used in measuring miRNAs were included. Furthermore, bibliographies of the articles were also retrieved for further relevant references. ResultsData reveal that miRNAs interfere with angiogenesis during early pregnancy by dysregulating pro-angiogenic factors (such as placental growth factor, vascular endothelial growth factor, fibroblast growth factor, transforming growth factor and insulin-like growth factor) and their receptors including Fms-like tyrosine kinase-1 and fibroblast growth factor receptor 1. In addition, miRNAs are also involved on high vascular pressure during preeclampsia by targeting several vasodilators such as prostacyclin, 17β-estradiol, hydrogen sulfide and nitric oxide, and inducing the production of angiotensin type I receptor agonistic autoantibodies. ConclusionData confirm that miRNAs are involved in pathobiology of preeclampsia including interference with angiogenesis during pre-clinical stage and induction of vascular resistance and vasoconstriction in clinical stage.

The Effect of Antenatal Multiple Micronutrient Supplementation on Placental Angiogenesis and Fetal Growth Factors in Rural Bangladesh

The Effect of Antenatal Multiple Micronutrient Supplementation on Placental Angiogenesis and Fetal Growth Factors in Rural Bangladesh

Angiogenesis in the placenta: the role of reactive oxygen species signaling.

Proper placental development and function are central to the health of both the mother and the fetus during pregnancy. A critical component of healthy placental function is the proper development of its vascular network. Poor vascularization of the placenta can lead to fetal growth restriction, preeclampsia, and in some cases fetal death. Therefore, understanding the mechanisms by which uterine stressors influence the development of the placental vasculature and contribute to placental dysfunction is of central importance to ensuring a healthy pregnancy. In this review we discuss how oxidative stress observed in maternal smoking, maternal obesity, and preeclampsia has been associated with aberrant angiogenesis and placental dysfunction resulting in adverse pregnancy outcomes. We also highlight that oxidative stress can influence the expression of a number of transcription factors important in mediating angiogenesis. Therefore, understanding how oxidative stress affects redox-sensitive transcription factors within the placenta may elucidate potential therapeutic targets for correcting abnormal placental angiogenesis and function.

The Rate of Pregnancy Loss in Von Willebrand Disease: A Cross-Sectional Study

Pregnancy and delivery represent a major hemostatic challenge in von Willebrand disease (VWD). In addition to maintaining adequate hemostasis, von Willebrand factor (VWF) is an important regulator of angiogenesis, with angiodysplasia contributing to morbidity in patients with VWD. Placental development is complex, with vascular development important for fetal growth and viability. It has been hypothesized that antepartum bleeding or abnormal placental angiogenesis may lead to pregnancy loss in women with VWD. Large studies have reported an increased risk of postpartum bleeding in patients with VWD, however, little information is available for rates of pregnancy loss. We conducted a cross-sectional study to determine the rate of pregnancy loss in women with VWD, when compared to a control population. We invited all women with VWD followed by the Southern Alberta Rare Blood and Bleeding Disorders Comprehensive Care Program to participate in an online or paper questionnaire, along with a control group of women without VWD identified through a low-risk obstetrical clinic in Calgary, Alberta. We included patients who were 18 years of age or older with a diagnosis of VWD, defined as VWF antigen and activity levels less than 50 percent or a historical diagnosis, in combination with a bleeding score of 4 or more (condensed MCMDM-1 bleeding questionnaire). Patients were excluded if they had no past pregnancies, no mailing address, or had an alternative bleeding disorder. Our 20-item questionnaire was reviewed and pre-tested by hematologists, obstetricians and laypeople. With patient consent, data was supplemented from clinical and hospital records to verify and expand on the information collected in the questionnaire. The primary outcome was the incidence of spontaneous abortion (fetal loss <20 weeks) or late pregnancy loss (≥20 weeks) in women with VWD. The secondary outcomes were antepartum and postpartum bleeding. Data on co-morbidities including placental abnormalities were also collected. Confidence intervals for proportions were calculated using the Wilson’s score method. Groups were compared using χ2 testing, with p values < 0.05 considered significant. Of the 98 women with VWD who met the study inclusion criteria, 31 (32%) completed the questionnaire. The mean bleeding score was 10.3 in VWD patients (SD 3.6). The majority (81%) of participants were diagnosed with Type 1 VWD, with 16% and 3% diagnosed as Type 2 and 3 VWD, respectively. Twenty-two women in the control group completed the questionnaire. The mean age at recruitment was 46.1 (SD 13.7) and 32.6 (SD 4.2) in the VWD and control group, respectively. There were 83 and 48 pregnancies in the VWD and control group, respectively. Two women in the VWD group and 1 woman in the control group had an elective pregnancy termination. In women with VWD, the rate of pregnancy loss was 24.7% out of 81 pregnancies (95% confidence interval 16.6-35.1), with 17 (85%) losses occurring less than 20 weeks, and 3 (15%) with unknown timing. In contrast, the rate of pregnancy loss in the control group was 12.8% (95% CI 5.96-25.17) (p=0.106), all occurring less than 20 weeks. In 83 pregnancies, the number of antepartum bleeding episodes in VWD women was 45 (29 first trimester, 9 second trimester, 7 third trimester), compared to the control group (9 first trimester, 3 second trimester, 1 third trimester) in 48 pregnancies. More women with VWD reported excessive postpartum bleeding compared to controls (56.7% versus 13.6%, p=0.002), with more delayed (>24 hour) bleeding post-delivery in women with VWD. In VWD women with and without pregnancy loss, there was no difference in mean bleeding score (9.7 vs. 10.9). There was also no difference in cases of pre-eclampsia, placental abruption or gestational hypertension in VWD women with and without pregnancy loss. Two VWD patients with previous pregnancy loss developed gastrointestinal angiodysplasia later in life. There was no significant increase in the rate of pregnancy loss in women with VWD, however, a larger cohort study is needed to confirm the rate of pregnancy loss before further conclusions can be made. Disclosures No relevant conflicts of interest to declare.

Editorial: New therapeutic targets for human placental angiogenesis disease.

Editorial: New therapeutic targets for human placental angiogenesis disease.

Placenta-derived angiogenic proteins and their contribution to the pathogenesis of preeclampsia.

Placental angiogenesis is critical to the success of human pregnancy. Angiogenesis is defined as the formation of new blood vessels from existing vasculature. Angiogenesis is necessary for the establishment of adequate placental perfusion, which is important for providing the optimum in utero environment to support fetal development. Defective placental angiogenesis is associated with several pregnancy complications, the most clinically important of which is preeclampsia; the multisystem disorder is characterized by maternal hypertension, proteinuria, and endothelial dysfunction. Here, we review our current understanding of several key angiogenic factors that are associated with placental angiogenesis. We also discuss their importance with respect to preeclampsia, where aberrant expression and release of these factors into the maternal circulation is thought to contribute to the pathogenesis and pathophysiology of preeclampsia.

M1/M2 macrophage polarity in normal and complicated pregnancy.

Tissue macrophages play an important role in all stages of pregnancy, including uterine stromal remodeling (decidualization) before embryo implantation, parturition, and post-partum uterine involution. The activation state and function of utero-placental macrophages are largely dependent on the local tissue microenvironment. Thus, macrophages are involved in a variety of activities such as regulation of immune cell activities, placental cell invasion, angiogenesis, and tissue remodeling. Disruption of the uterine microenvironment, particularly during the early stages of pregnancy (decidualization, implantation, and placentation) can have profound effects on macrophage activity and subsequently impact pregnancy outcome. In this review, we will provide an overview of the temporal and spatial regulation of utero-placental macrophage activation during normal pregnancy in human beings and rodents with a focus on more recent findings. We will also discuss the role of M1/M2 dysregulation within the intrauterine environment during adverse pregnancy outcomes.

Glucocorticoid exposure altered angiogenic factor expression via Akt/mTOR pathway in rat placenta

During pregnancy, glucocorticoids (GCs) are used for fetal lung maturation in women at risk of preterm labor. Exogenous GCs do not have exclusively beneficial effects and repeated use of GCs remains controversial. It has been observed that GC exposed rats have smaller placentas and intrauterine growth retarded fetuses. In this study, we questioned whether or not glucocorticoids effect placental angiogenesis mechanisms. One of the most important signaling pathways among several downstream of VEGFR-2 is PI3K/Akt which subsequently activates the mammalian target of rapamycin. Therefore, we hypothesized that overexposure to GCs may adversely affect placental angiogenesis mechanisms by regulating pro-angiogenic factors and their receptors via Akt/mTOR pathway. According to our results Dexamethasone, a synthetic glucocorticoid, administration led to a decrease in VEGF, PIGF expression during pregnancy. VEGFR2 expression was first decreased at gestational day 14 and afterwards increased at gestational days 16, 18 and 20 in rat placentas. These results are in accordance with the reduced phosphorylation of Akt, 4EBP1 and p70S6K. Dexamethasone injection also resulted in a reduction of VEGF, VEGFR1, and VEGFR2 mRNA expression at gestational days 14 and 20, but PIGF mRNA expression was not altered. Growth retarded fetuses seen in Dexamethasone treated pregnancies, may be a result of altered angiogenic factor expression of the placenta mediated via altered mTOR pathway signaling.

Abstract 094: Cox2 Inhibition During Decidualization Improves Fetal Growth Restriction In The BPH/5 Mouse Model Of Preeclampsia

Preeclampsia (PE) presents as maternal hypertension and proteinuria during the second half of pregnancy and often results in preterm delivery of a growth restricted baby. Despite being a leading cause of perinatal and maternal morbidity/mortality, the underlying mechanism(s) is unknown. Because signs resolve upon delivery of the placenta, abnormal placentation is widely accepted as the cause of PE. BPH/5 mice spontaneously develop the cardinal features of PE along with poor fetoplacental outcomes, such as fetal growth restriction. We have shown that BPH/5 implantation sites exhibit significant up-regulation of Ptgs2 (the gene encoding Cox2) at e7.5 as compared to C57. Since Cox2 and Cox2-derived prostaglandins (PGs) are crucial for uterine decidualization and placental angiogenesis, we tested the hypothesis that BPH/5 mice have dysregulated PG synthesis during decidualization and that this contributes to poor fetoplacental outcomes. Because e7.5 is considered the peak of decidualization, we designed experiments to selectively target Cox2 at this time in BPH/5 implantation sites. Administration of celecoxib by oral gavage at e6.5 (10mg/kg BW) caused a 2-fold reduction in Cox2 protein expression in BPH/5 implantation sites at e7.5 (n=3-4; p<0.05 vs BPH/5 veh). This had no effect on Cox2 levels in C57. This was associated with a significant reduction in PGE 2 synthesis (51.6±17.3 vs veh: 135.6±49.7 pg/mg), but not PGI 2 in e7.5 BPH/5 implantation sites (n=4-5; p<0.05). Neither PGE 2 nor PGI 2 synthesis was altered in C57 implantation sites. Furthermore, celecoxib improved fetal growth restriction in BPH/5 pups at e18.5 (1.108±0.091 vs veh: 1.036±0.021g), which was associated with an increase in placental weight (99.7±1.6 vs veh: 91.32±2.2mg) in BPH/5 females (n=20-38; p<0.05). These results provide evidence that Cox2 and PGE 2 play a key role in fetoplacental development in a mouse model of PE, and that celecoxib improves fetal outcomes in BPH/5 females. This highlights the significance of proper decidual angiogenesis and suggests that aberrations in these processes in early pregnancy may contribute to fetal growth restriction seen in PE pregnancies.

Role of NETRIN-4 on placental angiogenesis

s / Placenta 35 (2014) A1eA112 A16 stillbirths, such as the Relevant Condition at time of Death (ReCoDe) incorporate evidence of placental causes. Even using a modern classification system 15-20% of stillbirths remain “unexplained”; the role of the placenta in these cases is uncertain. Methods: A retrospective analysis of all cases (n1⁄4126) of singleton stillbirth in a tertiary UK obstetric unit from 2010-2013. Centiles for placental weight and birthweight:placental weight (BW:PW) were determined using population-based, gender and gestational-age-specific centile curves [1]. Cases of stillbirth were grouped according to ReCoDe classification for comparison. Result: The placental weight was 90th centile in 65/126 cases (52%). Respectively, the incidence of placental weight 90th centile for different stillbirth classifications was 79% and 58% for known FGR or placental insufficiency, 46% and 57% for other identified causes of stillbirth, and 49% and 47% for stillbirths of unknown cause. Conclusion: The incidence of placental weight and BW:PW ratio at the extremes of population-based centiles exceeded those anticipated; this persisted even in the absence of a clear diagnosis of FGR or placental insufficiency. The extreme of BW:PW ratio could be interpreted as “placental insufficiency” such that the placenta cannot meet the demand of the fetus. This provides further evidence of the presence of placental dysfunction in stillbirth. [1] Thompson et al. BJOG. 2007. 114(6):715-20. P1.18. ROLE OF NETRIN-4 ON PLACENTAL ANGIOGENESIS Mbarka Dakouane-Giudicelli , Guillaume Vallat , Sammy Si Nacer , Antoine Torre , Marion Vall ee , Jean-Jacque Feige , Nadia Alfaidy , Philippe de Mazancourt a Universit e de Versailles-St-Quentin en Yvelines, Versailles, France; b INSERM U1036 iRTSV /LAPV, Grenoble, France Objectives: Netrin-4 is a molecule involved in axon guidance, differentiation, cell growth and morphogenesis. Recently, netrin-4 was identified to play a key role in angiogenesis. These effects are mediated by Neogenin and UNC5B receptors. Recently, we have characterized netrin-4 and its receptors Neogenin and UNC5B expression in the human placenta. Netrin4 was observed in villous and extravillous cytotrophoblasts (EVT), syncytiotrophoblast (ST) and intravilli human placental endothelial cells (HPEC). The Neogenin receptor was localized to the ST and HPEC. UNC5B was observed in the villous cytotrophoblasts and HPEC. Considering the endothelial localisations of netrin 4 and ist receptors in the human placenta, we hypothezized that this systemmight play a role in the human placental angiogenesis. Methods: We isolated microvascular endothelial cells (HPEC) from term human placenta. Their endothelial origin was characterized using endothelial cells markers CD31, CD34, and vWF . First, we have demonstrated that HPEC cells express netrin-4, UNC5B and neogenin both at the mRNA and protein levels. Isolated HPEC cells were used to determine the effect of netrin4 on their proliferation, tube-like structure formation in matrigel, migration and endothelial cell spheroid sprouting in collagen. All these assayswere used as in vitromodel of angiogenesis andHPECwas incubated with different doses of netrin-4 (50-100-200-500ng/ml) added to the culture medium. Tube formation was quantified by counting the number of connections between endothelial cells after 6 hours (h), spheroid sprouting by counting outgrowth after 12h, migration by using wound healing after 12h and proliferation by counting cells after 24h treatment by netrin-4. Results:Netrin 4-mediated angiogenic processes in HPEC showed that this protein inhibits their proliferation, tubes formation, migration and spheroid sprouting, suggesting a potential role of netrin-4 in regulating placental angiogenesis. Conclusion: This is the first report of an anti-angiogenic activity of netrin4 in human placenta. This study will bring new insights into possible role of netrin-4 in placental angiogenesis-related pathologies of pregnancy such as intrauterine growth retardation and preeclampsia.

Development of the subplacenta in Galea spixii (Rodentia, Caviidae)

s / Placenta 35 (2014) A1eA112 A23 molecules in the fetal epithelium, and in the placental angiogenesis, despite the large distribution of the CAVs -1 and -2 in water buffalo placenta. Funding: FAPESP P1.40. DEVELOPMENT OF THE SUBPLACENTA IN GALEA SPIXII (RODENTIA, CAVIIDAE) Ferdinando Bezerra , Phelipe Favaron , Andrea Mess , Maria Angelica Miglino , Moacir de Oliveira a Department of Animal Science, Universidade Federal Rural do SemiArido, Mossoro, Rio Grande do Norte, Brazil; b Surgery Department, University of Sao Paulo, Sao Paulo, SP, Brazil The subplacenta of caviomorph rodents is considered to be the developmental origin for trophoblast invasion, which is relatively similar to the process in human beings. Objectives: We described subplacental development in a cavy species, Galea spixii. Methods: Tissues were collected from 12 females, ranging from day 15 to 55 of gestation. Samples were processed by means of histology, immunohistochemistry, cytochemistry, and electron microscopy. Results: On day 15 to 23, the subplacenta consisted of a single cytotrophoblast layer and a syncytium lining the maternal lacunae. Fetal circulation was present. On day 30, the subplacenta was more compact with well-defined border. Then it showed intense vascularisation. The lobules were composed by syncytiotrophoblast in the central part, and mesenchyme surrounded by cytotrophoblast at the borders of the organ. On day 45, degeneration of tissues was evident and syncytiotrophoblast was more abundant than cytotrophoblast. The syncytium was vacuolized and showed signs of apoptosis. Near term (days 53-55), more evident signs of cell death and reduction of subplacental tissue occurred. Proliferative activity of the subplacenta, evaluated by PCNA and AgNOR, was high early in early gestation and then continously decreased. Conclusion: In conclusion, the development of the subplacenta in Galea started early on reached a maximum around day 30 and became necrotic towards the end of gestation. Financial support: INCTC and NETCEM. P1.41-N. MORPHOLOGICAL AND VASCULAR CHANGES IN THE CORPUS LUTEUM DURING EARLY GESTATION OF BOVINE SCNT-DERIVED PREGNANCIES F abio Pinaffi, Izabelle Jardim, Juliano Sangalli, Rafael Sampaio, Flavio Meirelles, Luciano Silva University of Sao Paulo, Pirassununga, Sao Paulo,

Expression, regulation and function of Egr1 during implantation and decidualization in mice

Early growth response gene 1 (Egr1), a zinc finger transcriptional factor, plays an important role in regulating cell proliferation, differentiation and angiogenesis. Current data have shown that Egr1 is involved in follicular development, ovulation, luteinization and placental angiogenesis. However, the expression, regulation and function of Egr1 in mouse uterus during embryo implantation and decidualization are poorly understood. Here we showed that Egr1 was strongly expressed in the subluminal stroma surrounding the implanting blastocyst on day 5 of pregnancy. Injection of Egr1 siRNA into the mouse uterine horn could obviously reduce the number of implanted embryos and affect the uterine vascular permeability. Further study found that Egr1 played a role through influencing the expression of cyclooxygenase-2 (Cox-2), microsomal prostaglandin E synthase 1 (mPGES-1), vascular endothelial growth factor (Vegf), transformation related protein 53 (Trp53) and matrix metallopeptidase 9 (Mmp9) genes in the process of mouse embryo implantation. Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) might direct the expression of Egr1 in the uterine stromal cells. Under in vivo and in vitro artificial decidualization, Egr1 expression was significantly decreased. Overexpression of Egr1 downregulated the expression of decidual marker decidual/trophoblast PRL-related protein (Dtprp) in the uterine stromal cells, while inhibition of Egr1 upregulated the expression of Dtprp under in vitro decidualization. Estrogen and progesterone could regulate the expression of Egr1 in the ovariectomized mouse uterus and uterine stromal cells. These results suggest that Egr1 may be essential for embryo implantation and decidualization.

The integrative roles of chemokines at the maternal-fetal interface in early pregnancy.

Embryos express paternal antigens that are foreign to the mother, but the mother provides a special immune milieu at the fetal-maternal interface to permit rather than reject the embryo growth in the uterus until parturition by establishing precise crosstalk between the mother and the fetus. There are unanswered questions in the maintenance of pregnancy, including the poorly understood phenomenon of maternal tolerance to the allogeneic conceptus, and the remarkable biological roles of placental trophoblasts that invade the uterine wall. Chemokines are multifunctional molecules initially described as having a role in leukocyte trafficking and later found to participate in developmental processes such as differentiation and directed migration. It is increasingly evident that the gestational uterine microenvironment is characterized, at least in part, by the differential expression and secretion of chemokines that induce selective trafficking of leukocyte subsets to the maternal-fetal interface and regulate multiple events that are closely associated with normal pregnancy. Here, we review the expression and function of chemokines and their receptors at the maternal-fetal interface, with a special focus on chemokine as a key component in trophoblast invasiveness and placental angiogenesis, recruitment and instruction of immune cells so as to form a fetus-supporting milieu during pregnancy. The chemokine network is also involved in pregnancy complications.

FSH receptor (FSHR) expression in human extragonadal reproductive tissues and the developing placenta, and the impact of its deletion on pregnancy in mice.

Expression and function of the follicle-stimulating hormone receptor (FSHR) in females were long thought to be limited to the ovary. Here, however, we identify extragonadal FSHR in both the human female reproductive tract and the placenta, and test its physiological relevance in mice. We show that in nonpregnant women FSHR is present on: endothelial cells of blood vessels in the endometrium, myometrium, and cervix; endometrial glands of the proliferative and secretory endometrium; cervical glands and the cervical stroma; and (at low levels) stromal cells and muscle fibers of the myometrium. In pregnant women, placental FSHR was detected as early as 8-10 wk of gestation and continued through term. It was expressed on: endothelial cells in fetal portions of the placenta and the umbilical cord; epithelial cells of the amnion; decidualized cells surrounding the maternal arteries in the maternal decidua; and the stromal cells and muscle fibers of the myometrium, with particularly strong expression at term. These findings suggest that FSHR expression is upregulated during decidualization and upregulated in myometrium as a function of pregnancy. The presence of FSHR in the placental vasculature suggests a role in placental angiogenesis. Analysis of genetically modified mice in which Fshr is lacking in fetal portions of the placenta revealed adverse effects on fetoplacental development. Our data further demonstrate FSHB and CGA mRNAs in placenta and uterus, consistent with potential local sources of FSH. Collectively, our data suggest heretofore unappreciated roles of extragonadal FSHR in female reproductive physiology.

CRIM1, the antagonist of BMPs, is a potential risk factor of cancer.

Cysteine-rich motor neuron1 protein (CRIM1), a novel antagonist of bone morphogenetic proteins (BMPs), is reported to regulate the processing of BMPs preprotein into mature protein and the delivery of BMPs to the cell surface. Previous studies have shown that CRIM1 is an important player in regulating placental development, organogenesis, angiogenesis and kidney disease. Here, we propose that CRIM1 is a potential risk factor in cancer progression and metastasis. The epithelial-mesenchymal transition (EMT), which is characterized by the loss of epithelial phenotype and the acquisition of mesenchymal characteristics, is closely associated with invasion and metastasis of tumors. At the same time, it is hard for us to ignore the importance of angiogenesis in the genesis and progression of cancer. In this review we summarized the construction and previous researches of CRIM1. Furthermore, as it may be involved in tumor development and progression through its potential role in the EMT, capillary formation and angiogenesis maintenance, we proposed for the first time that CRIM1 may be a cancer related factor.

Is a low level of free thyroxine in the maternal circulation associated with altered endothelial function in gestational diabetes?

Synthesis of thyroid hormones, thyroxine (T4) and tri-iodothyronine (T3), in the human fetus starts from 17 to 19th weeks of gestation. Despite the majority of normal pregnant women reaching adequate levels of circulating thyroid hormones, in some cases, women with normal pregnancies have low level of free T4 during first trimester of pregnancy, suggesting that T4 action may be compromised in those women and their fetuses. In addition, pathological low levels of thyroid hormones are detected in isolated maternal hypothyroxemia (IMH) and clinical hypothyroidism. Nevertheless, human placenta regulates T3/T4 concentration in the fetal circulation by modulating the expression and activity of both thyroid hormone transporters (THT) and deiodinases. Then, placenta can control the availability of T3/T4 in the feto-placental circulation, and therefore may generate an adaptive response in cases where the mother courses with low levels of T4. In addition, T3/T4 might control vascular response in the placenta, in particularly endothelial cells may induce the synthesis and release of vasodilators such as nitric oxide (NO) or vasoconstrictors such as endothelin-1 mediated by these hormones. On the other hand, low levels of T4 have been associated with increase in gestational diabetes (GD) markers. Since GD is associated with impaired placental vascular function characterized by increased NO synthesis in placental arteries and veins, as well as elevated placental angiogenesis, it is unknown whether reduced T4 level at the maternal circulation could result in an altered placental endothelial function during GD. In this review, we analyze available information regarding thyroid hormones and endothelial dysfunction in GD; and propose that low maternal levels of T4 observed in GD may be compensated by increased placental availability of T3/T4 via elevation in the activity of THT and/or reduction in deiodinases in the feto-placental circulation.

Analysis of homeobox gene action may reveal novel angiogenic pathways in normal placental vasculature and in clinical pregnancy disorders associated with abnormal placental angiogenesis.

Homeobox genes are essential for both the development of the blood and lymphatic vascular systems, as well as for their maintenance in the adult. Homeobox genes comprise an important family of transcription factors, which are characterized by a well conserved DNA binding motif; the homeodomain. The specificity of the homeodomain allows the transcription factor to bind to the promoter regions of batteries of target genes and thereby regulates their expression. Target genes identified for homeodomain proteins have been shown to control fundamental cell processes such as proliferation, differentiation, and apoptosis. We and others have reported that homeobox genes are expressed in the placental vasculature, but our knowledge of their downstream target genes is limited. This review highlights the importance of studying the cellular and molecular mechanisms by which homeobox genes and their downstream targets may regulate important vascular cellular processes such as proliferation, migration, and endothelial tube formation, which are essential for placental vasculogenesis and angiogenesis. A better understanding of the molecular targets of homeobox genes may lead to new therapies for aberrant angiogenesis associated with clinically important pregnancy pathologies, including fetal growth restriction and preeclampsia.

Enhancement of the HIF-1α/15-LO/15-HETE Axis Promotes Hypoxia-Induced Endothelial Proliferation in Preeclamptic Pregnancy

Preeclampsia (PE) is an extremely serious condition in pregnant women and the leading cause of maternal and fetal morbidity and mortality. Despite active research, the etiological factors of this disorder remain elusive. The increased release of 15-hydroxyeicosatetraenoic acid (15-HETE) in the placenta of preeclamptic patients has been studied, but its exact role in PE pathogenesis remains unknown. Mounting evidence shows that PE is associated with placental hypoxia, impaired placental angiogenesis, and endothelial dysfunction. In this study, we confirmed the upregulated expression of hypoxia-inducible factor 1α (HIF-1α) and 15-lipoxygenase-1/2 (15-LO-1/2) in patients with PE. Production of the arachidonic acid metabolite, 15-HETE, also increased in the preeclamptic placenta, which suggests enhanced activation of the HIF-1α–15-LO–15-HETE axis. Furthermore, this study is the first to show that the umbilical cord of preeclamptic women contains significantly higher serum concentrations of 15-HETE than that of healthy pregnant women. The results also show that expression of 15-LO-1/2 is upregulated in both human umbilical vein endothelial cells (HUVECs) collected from preeclamptic women and in those cultured under hypoxic conditions. Exogenous 15-HETE promotes the migration of HUVECs and in vitro tube formation and promotes cell cycle progression from the G0/G1 phase to the G2/M + S phase, whereas the 15-LO inhibitor, NDGA, suppresses these effects. The HIF-1α/15-LO/15-HETE pathway is therefore significantly associated within the pathology of PE.

C0393: Modulation of Factors Involved in Placental Haemostasis and Angiogenesis by Low-Molecular-Weight Heparins

C0393: Modulation of Factors Involved in Placental Haemostasis and Angiogenesis by Low-Molecular-Weight Heparins