scholarly journals Placental development during early pregnancy in sheep: vascular growth and expression of angiogenic factors in maternal placenta

Reproduction ◽  
2010 ◽  
Vol 140 (1) ◽  
pp. 165-174 ◽  
Author(s):  
Anna T Grazul-Bilska ◽  
Pawel P Borowicz ◽  
Mary Lynn Johnson ◽  
Megan A Minten ◽  
Jerzy J Bilski ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fetal Growth ◽  
Early Pregnancy ◽  
Vascular Development ◽  
Hypoxia Inducible Factor ◽  
Angiogenic Factors ◽  
Placental Development ◽  
Proliferating Cells ◽  
Placental Angiogenesis ◽  
Tissue Area

Placental vascular development (angiogenesis) is critical for placental function and thus for normal embryonic/fetal growth and development. Specific environmental factors or use of assisted reproductive techniques may result in poor placental angiogenesis, which may contribute to embryonic losses and/or fetal growth retardation. Uterine tissues were collected on days 14, 16, 18, 20, 22, 24, 26, 28, and 30 after mating and on day 10 after estrus (nonpregnant controls) to determine vascular development and expression of several factors involved in the regulation of angiogenesis in the endometrium. Compared with controls, several measurements of endometrial vascularity increased (P<0.001) including vascular labeling index (LI; proportion of proliferating cells), the tissue area occupied by capillaries, area per capillary (capillary size), total capillary circumference per unit of tissue area, and expression of factor VIII (marker of endothelial cells), but capillary number decreased (P<0.001). Compared with controls, mRNA for placental growth factor, vascular endothelial growth factor receptors, angiopoietins (ANGPT) 1 and 2, ANGPT receptorTEK, endothelial nitric oxide synthase, and hypoxia-inducible factor 1α increased (P<0.05) during early pregnancy. Vascular LI was positively correlated (P<0.05) with several measurements of vascularity and with mRNA expression of angiogenic factors. These data indicate that endometrial angiogenesis, manifested by increased vascularity and increased expression of several factors involved in the regulation of angiogenesis, is initiated very early in pregnancy. This more complete description of early placental angiogenesis may provide the foundation for determining whether placental vascular development is altered in compromised pregnancies.

scholarly journals Placental development during early pregnancy in sheep: effects of embryo origin on vascularization

Reproduction ◽  
2014 ◽  
Vol 147 (5) ◽  
pp. 639-648 ◽  
Author(s):  
Anna T Grazul-Bilska ◽  
Mary Lynn Johnson ◽  
Pawel P Borowicz ◽  
Jerzy J Bilski ◽  
Taylor Cymbaluk ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mrna Expression ◽  
Assisted Reproductive Technologies ◽  
Vascular Development ◽  
Hypoxia Inducible Factor ◽  
Reproductive Technologies ◽  
Angiogenic Factors ◽  
Placental Development ◽  
Neuropilin 1

Utero-placental growth and vascular development are critical for pregnancy establishment that may be altered by various factors including assisted reproductive technologies (ART), nutrition, or others, leading to compromised pregnancy. We hypothesized that placental vascularization and expression of angiogenic factors are altered early in pregnancies after transfer of embryos created using selected ART methods. Pregnancies were achieved through natural mating (NAT), or transfer of embryos from NAT (NAT-ET), or IVF orin vitroactivation (IVA). Placental tissues were collected on day 22 of pregnancy. In maternal caruncles (CAR), vascular cell proliferation was less (P<0.05) for IVA than other groups. Compared with NAT, density of blood vessels was less (P<0.05) for IVF and IVA in fetal membranes (FM) and for NAT-ET, IVF, and IVA in CAR. In FM, mRNA expression was decreased (P<0.01–0.08) in NAT-ET, IVF, and IVA compared with NAT for vascular endothelial growth factor (VEGF) and its receptorFLT1, placental growth factor (PGF), neuropilin 1 (NP1) andNP2, angiopoietin 1 (ANGPT1) andANGPT2, endothelial nitric oxide synthase 3 (NOS3), hypoxia-inducible factor 1A (HIF1A), fibroblast growth factor 2 (FGF2), and its receptorFGFR2. In CAR, mRNA expression was decreased (P<0.01–0.05) in NAT-ET, IVF, and IVA compared with NAT forVEGF,FLT1,PGF,ANGPT1, andTEK. Decreased mRNA expression for 12 of 14 angiogenic factors across FM and CAR in NAT-ET, IVF, and IVA pregnancies was associated with reduced placental vascular development, which would lead to poor placental function and compromised fetal and placental growth and development.

106 ANGIOGENIC FACTOR mRNA EXPRESSION IN FETAL MEMBRANES IN EARLY PREGNANT SHEEP

2009 ◽  
Vol 21 (1) ◽  
pp. 153
Author(s):  
M. L. Johnson ◽  
L. P. Reynolds ◽  
M. A. Minten ◽  
P. P. Borowicz ◽  
D. A. Redmer ◽  
...  
Keyword(s):  
Growth Factor ◽  
Vascular Development ◽  
Fetal Loss ◽  
Angiogenic Factor ◽  
Fetal Membranes ◽  
Detailed Knowledge ◽  
Placental Development ◽  
Vegf Mrna ◽  
Placental Angiogenesis ◽  
Pregnant Sheep

Maternal and fetal placental development may be compromised by use of assisted reproductive techniques, including cloning, resulting in poor placental angiogenesis and subsequent high embryonic/fetal loss (Palmieri et al. 2007 Placenta 28, 577–584). Before changes in vascular development in placenta from compromised pregnancies can be understood, a detailed knowledge of regulation of angiogenesis in placental tissues from normal pregnancies is necessary. Therefore, this study determined the expression pattern of mRNA for several angiogenic factors and their receptors: vascular endothelial growth factor (VEGF) and receptor (R) 1 and 2; basic fibroblast growth factor (FGF2) and FGFRIIIc; angiopoietin (ANGPT) 1 and 2 and ANGPTR (Tie2); endothelial nitric oxide synthase (eNOS) and NO receptor GUCY1B3 in fetal membranes (FM; fetal placenta) collected on Days 16, 18, 20, 22, 24, 26, 28, and 30 after mating (n = 5 to 8/day). Fetal membranes were snap frozen for evaluation of gene expression using quantitative, real-time RT-PCR. VEGF mRNA was increased (P < 0.05) 2-fold on Days 28 and 30 compared with Days 16, 18, and 20, whereas VEGFR1 mRNA increased (P < 0.05) 25- to 50-fold on Days 28 and 30 compared with Day 16, and VEGFR2 mRNA was greatest (P < 0.05) on Day 22 compared with Days 16, 18, 28, and 30. FGF2 mRNA was 4-fold greater (P < 0.05) on Day 22 compared with Day 16; however, FGF2RIIIc was unchanged from Day 16 through 30. eNOS mRNA was greatest (P < 0.05) on Days 22 and 24 compared with Days 16 and 18, but GUCY1B3 mRNA was greatest (P < 0.05) on Day 18 compared with Days 20, 24, and 28. ANGPT1 mRNA increased (P < 0.05) 40-fold by Days 28 and 30 compared with Days 16 and 18. ANGPT2 mRNA was undetectable on Day 16, and increased (P < 0.05) 5-fold from Days 18 through 30. ANGPTR mRNA was greatest (P < 0.05) on Days 22 and 24 compared with Days 16 and 18. This description of expression of factors potentially regulating early placental angiogenesis during normal pregnancy in sheep will provide the foundation for understanding the dramatic increases in capillary cell proliferation and capillary size we have previously observed (unpublished) and for determining whether placental vascular development is altered in compromised pregnancies. USDA-NRI grant 2007-01215 to LPR and ATGB; NIH grant HL64141 to LPR and DAR; ND EPSCoR AURA grant to ATGB and MAM; ND Space Grant Fellowship Program award to MAM; and NIH grant P20 RR016741 (INBRE program of the NCRR, NIH).

scholarly journals Placental development during early pregnancy in sheep: cell proliferation, global methylation, and angiogenesis in the fetal placenta

Reproduction ◽  
2011 ◽  
Vol 141 (4) ◽  
pp. 529-540 ◽  
Author(s):  
Anna T Grazul-Bilska ◽  
Mary Lynn Johnson ◽  
Pawel P Borowicz ◽  
Megan Minten ◽  
Jerzy J Bilski ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Mrna Expression ◽  
Early Pregnancy ◽  
Cellular Proliferation ◽  
Dna Methyltransferases ◽  
Placental Development ◽  
Proliferating Cells ◽  
Global Methylation ◽  
Endothelial Nitric Oxide

To characterize early fetal placental development, gravid uterine tissues were collected from pregnant ewes every other day from day 16 to 30 after mating. Determination of 1) cell proliferation was based on Ki67 protein immunodetection; 2) global methylation was based on 5-methyl-cytosine (5mC) expression and mRNA expression for DNA methyltransferases (DNMTs)1,3a, and3b; and 3) vascular development was based on smooth muscle cell actin immunolocalization and on mRNA expression of several factors involved in the regulation of angiogenesis in fetal membranes (FMs). Throughout early pregnancy, the labeling index (proportion of proliferating cells) was very high (21%) and did not change. Expression of 5mC and mRNA forDNMT3bdecreased, but mRNA forDNMT1and3aincreased. Blood vessels were detected in FM on days 18–30 of pregnancy, and their number per tissue area did not change. The patterns of mRNA expression for placental growth factor, vascular endothelial growth factor, and their receptorsFLT1andKDR; angiopoietins 1 and 2 and their receptorTEK; endothelial nitric oxide synthase and the NO receptorGUCY13B; and hypoxia inducing factor 1 α changed in FM during early pregnancy. These data demonstrate high cellular proliferation rates, and changes in global methylation and mRNA expression of factors involved in the regulation of DNA methylation and angiogenesis in FM during early pregnancy. This description of cellular and molecular changes in FM during early pregnancy will provide the foundation for determining the basis of altered placental development in pregnancies compromised by environmental, genetic, or other factors.

scholarly journals Role of extracellular signal-regulated kinase and AKT cascades in regulating hypoxia-induced angiogenic factors produced by a trophoblast-derived cell line

2010 ◽  
Vol 206 (1) ◽  
pp. 131-140 ◽  
Author(s):  
Daisuke Fujita ◽  
Akiko Tanabe ◽  
Tatsuharu Sekijima ◽  
Hekiko Soen ◽  
Keijirou Narahara ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Line ◽  
Kinase Inhibitors ◽  
Transforming Growth Factor ◽  
Embryo Implantation ◽  
Hypoxia Inducible Factor ◽  
Transforming Growth Factor Β1 ◽  
Angiogenic Factors ◽  
Placental Development

During human pregnancy, trophoblasts play an important role in embryo implantation and placental development. Cytotrophoblast cells invade the uterine spiral arteries and differentiate into extravillous trophoblasts, resulting in the remodeling of the uterine vessels and fetoplacental vasculature. During early pregnancy, a physiologically hypoxic environment induces the production of angiogenic factors, such as vascular endothelial growth factor (VEGF), which are suggested to locally control the vascular remodeling. Endoglin, a cell-surface coreceptor for transforming growth factor-β1, is highly expressed in endothelial cells and syncytiotrophoblasts, and can be associated with endothelial nitric oxide synthase and vascular homeostasis. Several studies have recently suggested that some pregnancy-related complications, such as preeclampsia, have their origins early in pregnancy as a result of abnormalities in implantation and placental development. Although angiogenic factors are recognized as key molecules in placental development, little is known about the mechanism(s) of their regulation in trophoblasts. In this study, we elucidated the mechanisms underlying the regulation of VEGF and endoglin production under hypoxic conditions in the trophoblast-derived cell line, BeWo. We evaluated the role of the AKT–MTOR cascade and ERK kinase in the expression of VEGF and endoglin in response to hypoxia using various kinase inhibitors and small interfering RNA targeted against hypoxia-inducible factor (HIF)-1α (listed as HIF1A in Hugo Database). Our results suggest that both the phosphatidylinositol 3-kinase–AKT–MTOR–HIF-1α and ERK–HIF-1α signaling pathways are crucial for increasing VEGF and endoglin expression in response to hypoxia in BeWo cells.

Angiogenic Gene Expression in Down Syndrome Fetal Hearts

2015 ◽  
Vol 40 (1) ◽  
pp. 21-27 ◽  
Author(s):  
Olga Sánchez ◽  
Carmen Domínguez ◽  
Aina Ruiz ◽  
Irene Ribera ◽  
Jaume Alijotas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Down Syndrome ◽  
Growth Factor ◽  
Heart Defects ◽  
Hypoxia Inducible Factor ◽  
Transcript Level ◽  
Heart Tissue ◽  
Angiogenic Factors ◽  
Heme Oxygenase 1 ◽  
Endothelial Growth Factor

Introduction: Forty percent of Down syndrome (DS) fetuses have congenital heart defects (CHD). An abnormal angiogenic environment has been described in euploid fetuses with CHD. However, the underlying pathophysiologic pathway that contributes to CHD in DS remains unknown. The objective was to compare the expression of angiogenic factors and chronic hypoxia genes in heart tissue from DS and euploid fetuses with and without CHD. Methods: The gene expression profile was determined by real-time PCR quantification in heart tissue from 33 fetuses with DS, 23 euploid fetuses with CHD and 23 control fetuses. Results: Angiogenic factors mRNA expression was significantly increased in the DS group compared to the controls (soluble fms-like tyrosine kinase-1, 81%, p = 0.007; vascular endothelial growth factor A, 57%, p = 0.006, and placental growth factor, 32%, p = 0.0227). Significant increases in the transcript level of hypoxia-inducible factor-2α and heme oxygenase 1 were also observed in the DS group compared to the controls. The expression of angiogenic factors was similar in DS fetuses and CHD euploid fetuses with CHD. Conclusion: Abnormal angiogenesis was detected in the hearts of DS fetuses with and without CHD. Our results suggest that DS determines an intrinsically angiogenic impairment that may be present in the fetal heart.

scholarly journals 273.Insulin-like growth factor treatment of pregnant guinea pigs during early pregnancy promotes fetal growth

2004 ◽  
Vol 16 (9) ◽  
pp. 273
Author(s):  
A. N. Sferruzzi-Perri ◽  
J. A. Owens ◽  
J. S. Robinson ◽  
C. T. Roberts
Keyword(s):  
Growth Factor ◽  
Fetal Growth ◽  
Early Pregnancy ◽  
Guinea Pigs ◽  
Placental Weight ◽  
Fetal Weight ◽  
Abdominal Circumference ◽  
Insulin Like Growth Factor ◽  
Crown Rump Length ◽  
Igf I

Insulin-like growth factor (IGF)-II is an important regulator of growth in many tissues and is abundantly expressed in the placenta during pregnancy. Gene ablation studies performed in mice have shown that IGF-II deficiency results in both impaired fetal and placental growth, whereas deficiency in IGF-I reduces fetal growth only. Conversely, maternal IGF supplementation in early pregnancy in the guinea pig increases placental and fetal size by mid pregnancy. This study aimed to determine whether these anabolic effects persist into late pregnancy after cessation of treatment. On Day 20 of pregnancy, mothers were anaesthetised and a mini osmotic pump was implanted subcutaneously, to deliver 1mg/kg/day IGF-I (n = 7), IGF-II (n = 9) or vehicle (n = 7) for 17 days. Guinea pigs were killed on Day 62 of pregnancy (term ~67 days). Fetal and placental weights, and maternal and fetal body composition, were measured. Total litter size was unaffected by IGF treatment; however, IGF-II increased the number of viable fetuses by 26% (P = 0.01). After adjusting for the number of viable pups per litter, maternal IGF treatment increased fetal growth by increasing abdominal circumference, crown-rump length and fetal weight (fetal weight: IGF-I 79+/–2.5 g; IGF-II 78+/–2.6 g; vs vehicle 68+/–2.5 g, P = 0.02). IGF treatment did not alter absolute or relative fetal organ weights. IGF-I reduced placental weight by 9% and IGF-II increased it by 9%, but not significantly. IGF-I increased the fetal weight�:�placental weight ratio (19+/–0.9 vs 15+/–0.9, respectively P = 0.043). IGF treatment did not affect maternal weight gain during pregnancy nor net carcass weight; however, IGF-I reduced maternal lung and adipose tissue weights. In conclusion, maternal IGF-II treatment during early pregnancy improved fetal growth into late gestation, possibly by modulating placental efficiency. As poor placental development is implicated in fetal growth restriction, increasing maternal IGF abundance in early to mid pregnancy may be a potential therapeutic approach to placental insufficiency.

scholarly journals Maternal growth factor regulation of human placental development and fetal growth

2010 ◽  
Vol 207 (1) ◽  
pp. 1-16 ◽  
Author(s):  
Karen Forbes ◽  
Melissa Westwood
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Fetal Growth ◽  
Mechanism Of Action ◽  
Normal Development ◽  
Receptor Interaction ◽  
Placental Development ◽  
Maternal Circulation ◽  
Successful Pregnancy ◽  
And Function

Normal development and function of the placenta is critical to achieving a successful pregnancy, as normal fetal growth depends directly on the transfer of nutrients from mother to fetus via this organ. Recently, it has become apparent from both animal and human studies that growth factors within the maternal circulation, for example the IGFs, are important regulators of placental development and function. Although these factors act via distinct receptors to exert their effects, the downstream molecules activated upon ligand/receptor interaction are common to many growth factors. The expression of numerous signaling molecules is altered in the placentas from pregnancies affected by the fetal growth complications, fetal growth restriction, and macrosomia. Thus, targeting these molecules may lead to more effective treatments for complications of pregnancy associated with altered placental development. Here, we review the maternal growth factors required for placental development and discuss their mechanism of action.

scholarly journals Expression of Hypoxia-Inducible Factor (HIF)-1αand Vascular Endothelial Growth Factor (VEGF)-D As Outcome Predictors in Resected Esophageal Squamous Cell Carcinoma

2008 ◽  
Vol 25 (3) ◽  
pp. 141-148 ◽  
Author(s):  
Ching Tzao ◽  
Shih-Chun Lee ◽  
Ho-Jui Tung ◽  
Han-Shui Hsu ◽  
Wen-Hu Hsu ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Squamous Cell ◽  
Cell Cancer ◽  
Hypoxia Inducible Factor ◽  
Prognostic Significance ◽  
Tumor Stage ◽  
Angiogenic Factors ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Hypoxia-inducible factor (HIF)-1αand vascular endothelial growth factor (VEGF) are important angiogenic factors in human cancers. Relative to VEGF-C, prognostic significance of VEGF-D expression and its association with HIF-1αexpression remain elusive in esophageal squamous cell cancer (ESCC). We studied expression of HIF-1αand VEGF-D using immunohistochemistry in 85 resected ESCC specimens and correlated results with patients' clinicopathologic parameters and survival. Association between expression of HIF-1αand VEGF-D was investigated using a concordance analysis. High expression of HIF-1αand VEGF-D was observed in 52 (61.2%) and 56 (65.9%) patients, respectively. HIF-1αexpression correlated well with tumor stage (P= 0.041), whereas VEGF-D expression correlated with tumor stage (P= 0.027) and N status (P= 0.019). Groups of high HIF-1αand VEGF-D showed worse survivals than those of low expression (P= 0.002 and 0.001, respectively). Multivariate analysis supported expression of HIF-1αand VEGF-D as significant survival predictors (P= 0.044 and 0.035, respectively). A concordance rate of 69.5% was observed between expression of HIF-1αand VEGF-D. In conclusion, protein expression of HIF-1αand VEGF-D are independent prognostic predictors. An association between expression of HIF-1αand VEGF-D suggests that these two angiogenic factors are essential in progression of ESCC.

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