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: 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 Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes.

1995 ◽  
Vol 15 (10) ◽  
pp. 5363-5368 ◽  
Author(s):  
I Stein ◽  
M Neeman ◽  
D Shweiki ◽  
A Itin ◽  
E Keshet
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Half Life ◽  
Angiogenic Factor ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Vegf Mrna ◽  
Glut 1 ◽  
Induced Genes ◽  
Endothelial Growth Factor

Expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen and a potent angiogenic factor, is upregulated in response to a hypoxic or hypoglycemic stress. Here we show that the increase in steady-state levels of VEGF mRNA is partly due to transcriptional activation but mostly due to increase in mRNA stability. Both oxygen and glucose deficiencies result in extension of the VEGF mRNA half-life in a protein synthesis-dependent manner. Viewing VEGF as a stress-induced gene, we compared its mode of regulation with that of other stress-induced genes. Results showed that under nonstressed conditions, VEGF shares with the glucose transporter GLUT-1 a relatively short half-life (0.64 and 0.52 h, respectively), which is extended fourfold and more than eightfold, respectively, when cells are deprived of either oxygen or glucose. In contrast, the mRNAs of another hypoxia-inducible and hypoglycemia-inducible gene, grp78, as well as that of HSP70, were not stabilized by these metabolic insults. To show that VEGF and GLUT-1 are coinduced in differentially stressed microenvironments, multicell spheroids representing a clonal population of glioma cells in which each cell layer is differentially stressed were analyzed by in situ hybridization. Cellular microenvironments conducive to induction of VEGF and GLUT-1 were completely coincidental. These findings show that two different consequences of tissue ischemia, namely, hypoxia and glucose deprivation, induce VEGF and GLUT-1 expression by similar mechanisms. These proteins function, in turn, to satisfy the tissue needs through expanding its vasculature and improving its glucose utilization, respectively.

scholarly journals The SK3 channel promotes placental vascularization by enhancing secretion of angiogenic factors

2014 ◽  
Vol 307 (10) ◽  
pp. E935-E943 ◽  
Author(s):  
Cara C. Rada ◽  
Grace Murray ◽  
Sarah K. England
Keyword(s):  
Growth Factor ◽  
Vascular Function ◽  
Fetal Loss ◽  
High Rate ◽  
Angiogenic Factor ◽  
Soluble Form ◽  
Vegf Receptor ◽  
Wild Type ◽  
Placental Perfusion ◽  
Sk3 Channel

Proper placental perfusion is essential for fetal exchange of oxygen, nutrients, and waste with the maternal circulation. Impairment of uteroplacental vascular function can lead to pregnancy complications, including preeclampsia and intrauterine growth restriction (IUGR). Potassium channels have been recognized as regulators of vascular proliferation, angiogenesis, and secretion of vasoactive factors, and their dysfunction may underlie pregnancy-related vascular diseases. Overexpression of one channel in particular, the small-conductance calcium-activated potassium channel 3 (SK3), is known to increase vascularization in mice, and mice overexpressing the SK3 channel (SK3T/T mice) have a high rate of fetal demise and IUGR. Here, we show that overexpression of SK3 causes fetal loss through abnormal placental vascularization. We previously reported that, at pregnancy day 14, placentas isolated from SK3T/T mice are smaller than those obtained from wild-type mice. In this study, histological analysis reveals that SK3T/− placentas at this stage have abnormal placental morphology, and microcomputed tomography shows that these placentas have significantly larger and more blood vessels than those from wild-type mice. To identify the mechanism by which these vascularization defects occur, we measured levels of vascular endothelial growth factor (VEGF), placental growth factor, and the soluble form of VEGF receptor 1 (sFlt-1), which must be tightly regulated to ensure proper placental development. Our data reveal that overexpression of SK3 alters systemic and placental ratios of the angiogenic factor VEGF to antiangiogenic factor sFlt-1 throughout pregnancy. Additionally, we observe increased expression of hypoxia-inducing factor 2α in SK3T/− placentas. We conclude that the SK3 channel modulates placental vascular development and fetal health by altering VEGF signaling.

scholarly journals The Multiple Roles of EG-VEGF/PROK1 in Normal and Pathological Placental Angiogenesis

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Nadia Alfaidy ◽  
Pascale Hoffmann ◽  
Houssine Boufettal ◽  
Naima Samouh ◽  
Touria Aboussaouira ◽  
...  
Keyword(s):  
Multiple Roles ◽  
Angiogenic Factor ◽  
Endocrine Gland ◽  
Placental Development ◽  
Placental Angiogenesis ◽  
Trophoblastic Diseases ◽  
Potential Biomarker ◽  
Gestational Trophoblastic Diseases ◽  
Vasculogenesis And Angiogenesis ◽  
Endothelial Growth Factor

Placentation is associated with several steps of vascular adaptations throughout pregnancy. These vascular changes occur both on the maternal and fetal sides, consisting of maternal uterine spiral arteries remodeling and placental vasculogenesis and angiogenesis, respectively. Placental angiogenesis is a pivotal process for efficient fetomaternal exchanges and placental development. This process is finely controlled throughout pregnancy, and it involves ubiquitous and pregnancy-specific angiogenic factors. In the last decade, endocrine gland derived vascular endothelial growth factor (EG-VEGF), also called prokineticin 1 (PROK1), has emerged as specific placental angiogenic factor that controls many aspects of normal and pathological placental angiogenesis such as recurrent pregnancy loss (RPL), gestational trophoblastic diseases (GTD), fetal growth restriction (FGR), and preeclampsia (PE). This review recapitulates EG-VEGF mediated-angiogenesis within the placenta and at the fetomaternal interface and proposes that its deregulation might contribute to the pathogenesis of several placental diseases including FGR and PE. More importantly this paper argues for EG-VEGF clinical relevance as a potential biomarker of the onset of pregnancy pathologies and discusses its potential usefulness for future therapeutic directions.

scholarly journals Conditional Mutation of Hand1 in the Mouse Placenta Disrupts Placental Vascular Development Resulting in Fetal Loss in Both Early and Late Pregnancy

2021 ◽  
Vol 22 (17) ◽  
pp. 9532
Author(s):  
Jennifer A. Courtney ◽  
Rebecca L. Wilson ◽  
James Cnota ◽  
Helen N. Jones
Keyword(s):  
Heart Defects ◽  
Fetal Loss ◽  
Late Pregnancy ◽  
Vessel Density ◽  
Angiogenic Factor ◽  
Placental Development ◽  
Fetal Demise ◽  
Exchange Area ◽  
First Time ◽  
Sufficient Oxygen

Congenital heart defects (CHD) affect approximately 1% of all live births, and often require complex surgeries at birth. We have previously demonstrated abnormal placental vascularization in human placentas from fetuses diagnosed with CHD. Hand1 has roles in both heart and placental development and is implicated in CHD development. We utilized two conditionally activated Hand1A126fs/+ murine mutant models to investigate the importance of cell-specific Hand1 on placental development in early (Nkx2-5Cre) and late (Cdh5Cre) pregnancy. Embryonic lethality occurred in Nkx2-5Cre/Hand1A126fs/+ embryos with marked fetal demise occurring after E10.5 due to a failure in placental labyrinth formation and therefore the inability to switch to hemotrophic nutrition or maintain sufficient oxygen transfer to the fetus. Labyrinthine vessels failed to develop appropriately and vessel density was significantly lower by day E12.5. In late pregnancy, the occurrence of Cdh5Cre+;Hand1A126fs/+ fetuses was reduced from 29% at E12.5 to 20% at E18.5 and remaining fetuses exhibited reduced fetal and placental weights, labyrinth vessel density and placenta angiogenic factor mRNA expression. Our results demonstrate for the first time the necessity of Hand1 in both establishment and remodeling of the exchange area beyond early pregnancy and in patterning vascularization of the placental labyrinth crucial for maintaining pregnancy and successful fetal growth.

Hydrogen peroxide stimulates macrophage vascular endothelial growth factor release

2001 ◽  
Vol 280 (5) ◽  
pp. H2357-H2363 ◽  
Author(s):  
Michael Cho ◽  
Thomas K. Hunt ◽  
M. Zamirul Hussain
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Gene Promoter ◽  
Peritoneal Macrophages ◽  
Angiogenic Factor ◽  
Vascular Endothelial ◽  
Vegf Mrna ◽  
Significant Difference ◽  
Activated Neutrophils ◽  
Endothelial Growth Factor

Neutrophils gather at the wound site shortly after trauma and release bactericidal reactive oxygen species (ROS) and H2O2to kill bacteria and prevent infection. Macrophages arrive at the wound in response to environmental stimuli, phagocytose foreign particles, and release vascular endothelial growth factor (VEGF), an angiogenic factor crucial for wound healing. Because oxidants are released early in inflammation and have been found to regulate transcription factors, we investigated a possible role of H2O2in VEGF stimulation. Human U937 macrophages exposed to H2O2and allowed to recover in H2O2-free medium rapidly showed an increase in VEGF mRNA. The H2O2-mediated mRNA increase was dose dependent, blocked by catalase, and associated with elevated VEGF in conditioned media. The increase in VEGF was also found in primary rat peritoneal macrophages and the RAW 264.7 murine macrophage cell line. Transcriptional inhibition with actinomycin D revealed no significant difference in mRNA half-life. Transient transfections with a 1.6-kb VEGF promoter-luciferase construct (Shima DT, Kuroki M, Deutsch U, Ng YS, Adamis AP, and D'Amore PA. J Biol Chem 271: 3877–3883, 1996) showed a ninefold stimulation of VEGF gene promoter activity. We concluded that H2O2increases macrophage VEGF through an oxidant induction of VEGF promoter. This oxidant stimulation can be mediated by activated neutrophils.

scholarly journals Balanced levels of nerve growth factor are required for normal pregnancy progression

Reproduction ◽  
2014 ◽  
Vol 148 (2) ◽  
pp. 179-189 ◽  
Author(s):  
Pierre Frank ◽  
Gabriela Barrientos ◽  
Irene Tirado-González ◽  
Marie Cohen ◽  
Petra Moschansky ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Ovarian Function ◽  
Critical Role ◽  
Fetal Loss ◽  
Placental Tissue ◽  
Normal Pregnancy ◽  
Placental Development ◽  
Local Inflammatory Response ◽  
Nerve Growth

Nerve growth factor (NGF), the first identified member of the family of neurotrophins, is thought to play a critical role in the initiation of the decidual response in stress-challenged pregnant mice. However, the contribution of this pathway to physiological events during the establishment and maintenance of pregnancy remains largely elusive. Using NGF depletion and supplementation strategies alternatively, in this study, we demonstrated that a successful pregnancy is sensitive to disturbances in NGF levels in mice. Treatment with NGF further boosted fetal loss rates in the high-abortion rate CBA/J x DBA/2J mouse model by amplifying a local inflammatory response through recruitment of NGF-expressing immune cells, increased decidual innervation with substance P+ nerve fibres and a Th1 cytokine shift. Similarly, treatment with a NGF-neutralising antibody in BALB/c-mated CBA/J mice, a normal-pregnancy model, also induced abortions associated with increased infiltration of tropomyosin kinase receptor A-expressing NK cells to the decidua. Importantly, in neither of the models, pregnancy loss was associated with defective ovarian function, angiogenesis or placental development. We further demonstrated that spontaneous abortion in humans is associated with up-regulated synthesis and an aberrant distribution of NGF in placental tissue. Thus, a local threshold of NGF expression seems to be necessary to ensure maternal tolerance in healthy pregnancies, but when surpassed may result in fetal rejection due to exacerbated inflammation.

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.

Disrupted pulmonary vascular development and pulmonary hypertension in transgenic mice overexpressing transforming growth factor-α

2003 ◽  
Vol 285 (5) ◽  
pp. L1046-L1054 ◽  
Author(s):  
Timothy D. Le Cras ◽  
William D. Hardie ◽  
Karen Fagan ◽  
Jeffrey A. Whitsett ◽  
Thomas R. Korfhagen
Keyword(s):  
Pulmonary Hypertension ◽  
Growth Factor ◽  
Transgenic Mice ◽  
Vascular Disease ◽  
Vascular Remodeling ◽  
Transforming Growth Factor ◽  
Vascular Development ◽  
Angiogenic Factor ◽  
Pulmonary Vascular Disease ◽  
Pulmonary Vascular Development

Pulmonary vascular disease plays a major role in morbidity and mortality in infant and adult lung diseases in which increased levels of transforming growth factor (TGF)-α and its receptor EGFR have been associated. The aim of this study was to determine whether overexpression of TGF-α disrupts pulmonary vascular development and causes pulmonary hypertension. Lung-specific expression of TGF-α in transgenic mice was driven with the human surfactant protein (SP)-C promoter. Pulmonary arteriograms and arterial counts show that pulmonary vascular development was severely disrupted in TGF-α mice. TGF-α mice developed severe pulmonary hypertension and vascular remodeling characterized by abnormally extensive muscularization of small pulmonary arteries. Pulmonary vascular development was significantly improved and pulmonary hypertension and vascular remodeling were prevented in bitransgenic mice expressing both TGF-α and a dominant-negative mutant EGF receptor under the control of the SP-C promoter. Vascular endothelial growth factor (VEGF-A), an important angiogenic factor produced by the distal epithelium, was decreased in the lungs of TGF-α adults and in the lungs of infant TGF-α mice before detectable abnormalities in pulmonary vascular development. Hence, overexpression of TGF-α caused severe pulmonary vascular disease, which was mediated through EGFR signaling in distal epithelial cells. Reductions in VEGF may contribute to the pathogenesis of pulmonary vascular disease in TGF-α mice.

63 Inhibition of CXCR4 at the fetal-maternal interface during placentation results in altered production of vascular endothelial growth factor receptors in the placenta on Day 90 of pregnancy

2020 ◽  
Vol 32 (2) ◽  
pp. 157
Author(s):  
J. M. Ervin ◽  
S. Z. McIntosh ◽  
C. L. Runyan ◽  
R. L. Ashley
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Animal Model ◽  
Growth Factor ◽  
Day Treatment ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Placental Development ◽  
Fetal Survival ◽  
Pregnant Sheep ◽  
Endothelial Growth Factor

Placental development is characterised by extensive angiogenesis and vascularization; if these processes are compromised, placental dysfunction occurs, which is the underlying cause of complications such as preeclampsia and intrauterine growth restriction. The signalling axis initiated by chemokine ligand 12 (CXCL12) and its receptor CXCR4 stimulate angiogenesis critical to placental vascularization. Our laboratory and others demonstrated stimulation of vascular endothelial growth factor (VEGF) synthesis by CXCL12/CXCR4 signalling, and recently, we reported less production of the VEGF receptor, FLT-1, on Day 20 in pregnant sheep following interference of intrauterine CXCL12-dependent signalling. While no animal model fully recapitulates human placentation, the sheep is arguably the most applicable animal model to study fetal-maternal interactions and placentation. Based on our studies, we hypothesised that inhibiting CXCR4 at the fetal-maternal interface during initial placentation alters placental production of VEGF receptors, FLT-1 and KDR, at mid-gestation. To test this hypothesis, AMD3100, a CXCR4 antagonist, was used to elucidate the role of CXCL12/CXCR4 signalling at the ovine fetal-maternal interface. On Day 12 post-breeding, osmotic pumps were surgically installed and delivered either AMD3100 or phosphate-buffered saline (PBS) into the uterine lumen ipsilateral to the corpus luteum for either 7 days (n=7 PBS and n=8 AMD3100) or 14 days (n=7 PBS and n=8 AMD3100). The objectives were to determine whether disruption of the CXCL12/CXCR4 axis during placentation affects fetal survival and alters VEGF receptor synthesis and whether duration of CXCR4 inhibition affects placental vascular remodelling. On Day 90 of pregnancy, ewes were anaesthetised; reproductive tracts were removed; and maternal caruncle (CAR) and fetal cotyledon (COT) components were separated, snap frozen in liquid nitrogen, and stored at −80°C until protein isolation. Pregnancy success was not affected by treatment or duration of treatment (71% PBS vs. 62% AMD3100 for 7 days; 85% PBS vs. 62% AMD3100 for 14 days). In addition, fetal weight on Day 90 (530.8±28.2 g PBS vs. 540.5±20.3g AMD3100 for 7 days; 494.3±23.9g PBS vs. 532.7±11.8g AMD3100 for 14 days) was not affected by treatment. Immunoblotting was used to detect protein abundance, and an unpaired two-tailed Student's t-test was used to determine significant changes. Greater FLT-1 (P&lt;0.05) was evident in CAR and COT tissue on Day 90 for both the 7-day treatment (0.92±0.16 CAR PBS vs. 1.48±0.18 CAR AMD3100; 0.12±0.16 COT PBS vs. 0.62±0.16 COT AMD3100) and the 14-day treatment (0.18±0.05 CAR PBS vs. 0.43±0.001 CAR AMD3100; 0.04±0.005 COT PBS vs. 0.11±0.02 COT AMD3100) of CXCR4 inhibition compared with controls, whereas KDR levels did not change (P&gt;0.05). Interestingly, elevated FLT-1, but not KDR, is a marker of preeclampsia in women, and because of its role as a VEGF scavenger, overexpression of FLT-1 often leads to an anti-angiogenic state. We suggest that CXCL12/CXCR4 signalling during initial placental development serves as an upstream regulator of placental vascularization, thereby ensuring appropriate placental development.

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