scholarly journals Endothelial tubulogenesis within fibrin gels specifically requires the activity of membrane-type-matrix metalloproteinases (MT-MMPs)

2002 ◽  
Vol 115 (17) ◽  
pp. 3427-3438 ◽  
Author(s):  
Marc A. Lafleur ◽  
Madeleine M. Handsley ◽  
Vera Knäuper ◽  
Gillian Murphy ◽  
Dylan R. Edwards
Keyword(s):  
Growth Factor ◽  
Cell Types ◽  
Tube Formation ◽  
Matrix Metalloproteinase 2 ◽  
Mrna Levels ◽  
Fibrin Gels ◽  
Fibrin Matrix ◽  
Inhibition Of Angiogenesis ◽  
Membrane Type ◽  
Endothelial Growth Factor

Macro- and microvascular endothelial cells (EC) formed tubular structures when cultured within a 3D fibrin matrix, a process that was enhanced by vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2),hepatocyte growth factor/scatter factor (HGF/SF) and an angiogenic cocktail composed of nine angiogenic factors. Endothelial tubulogenesis was also increased in co-culture with tumour cells such as U87 glioma cells, but not with non-tumorigenic cell types such as Madin-Darby canine kidney (MDCK)epithelial cells. VEGF/FGF-2-stimulated tube formation was dependent on metalloproteinase function [it is inhibited by the addition of tissue inhibitor of metalloproteinases-2 (TIMP-2)], whereas aprotinin, E64[trans-epoxysuccinyl-L-leucylamido (4-guanidino)-butane] and pepstatin had no effect. In addition, TIMP-4 also inhibited tubulogenesis, but TIMP-1 or the C-terminal haemopexin domain of matrix metalloproteinase-2 (MMP-2) (PEX) and an anti-MMP-2 function-blocking antibody were unable to block tube formation. This suggests that MMP-2 and other soluble MMPs are not essential for tubulogenesis in fibrin gels, instead TIMP-1-insensitive MMPs, such as members of the membrane type-MMPs (MT-MMP) sub-group (MT1-, MT2-, MT3- or MT5-MMP),are required for this process. Further support for a role for MT1-MMP in endothelial tubulogenesis is that recombinant Y36G N-terminal TIMP-2 mutant protein, which retains an essentially unaltered apparent inhibition constant(Kiapp) for several MMPs compared to wild-type N-TIMP-2 but is a 40-fold poorer inhibitor of MT1-MMP, was unable to block tubulogenesis. Furthermore, when EC were cultured within fibrin gels, the mRNA levels of several MMPs (including MT1-MMP, MT2-MMP, MT3-MMP and MMP-2)increased during tubulogenesis. Therefore MT-MMPs and specifically MT1-MMP are likely candidates for involvement during endothelial tubulogenesis within a fibrin matrix, and thus their blockade may be a viable strategy for inhibition of angiogenesis.

Alteration in angiogenic potential of granulosa-lutein cells and follicular fluid contributes to luteal defects in polycystic ovary syndrome

2020 ◽  
Author(s):  
Krutika Patil ◽  
Indira Hinduja ◽  
Srabani Mukherjee
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Polycystic Ovary ◽  
Tube Formation ◽  
Vascular Endothelial ◽  
Transcript Levels ◽  
Angiogenic Potential ◽  
Angiogenic Genes ◽  
Endothelial Growth Factor

Abstract STUDY QUESTION Is angiogenic potential of follicular fluid (FF) and granulosa-lutein cells (GLCs) altered in polycystic ovary syndrome (PCOS) and does it play a role in corpus luteum (CL) defect observed in them? SUMMARY ANSWER FF and GLCs of women with PCOS show reduced expression of pro-angiogenic factors compared to controls and exhibit a diminished capacity to induce angiogenesis. WHAT IS KNOWN ALREADY In women with PCOS, CL insufficiency and frequent miscarriage are reported, which may be due to defect in CL. The development of new blood vessels is essential to promote ovarian folliculogenesis and functional CL formation. The vasculature formation in CL which is important for its function is still unexplored in these women. STUDY DESIGN, SIZE, DURATION This case-control study was conducted in 30 healthy control women and 30 women with PCOS undergoing controlled ovarian hyperstimulation for IVF. The FF, GLCs and serum were collected from all participants during ovum pick up. PARTICIPANTS/MATERIALS, SETTING, METHODS The capacity of FF to induce angiogenesis was assessed by measuring levels of pro-angiogenic factors vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) and its tube formation and wound healing potential using human umbilical vein endothelial cells (HUVECs). We investigated the angiogenic potential and endothelial cell-like nature of GLCs using several approaches such as the expression of angiogenic genes by quantitative PCR, DiI-conjugated acetylated low-density lipoproteins (Dil-Ac-LDL) internalization assay, tube formation assay, expression of endothelial cell markers by immunofluorescence analysis. In addition, correlation of transcript levels of angiogenic genes with oocyte parameters was studied. MAIN RESULTS AND THE ROLE OF CHANCE FF and serum levels of VEGF and FGF2 were significantly higher and lower, respectively, in PCOS compared to controls. The tube formation and wound healing capacity of HUVECs was found to be reduced when measured after supplementation with FF of women with PCOS compared to controls. This suggests a decreased angiogenic capacity of FF in women with PCOS. Tube formation (P = 0.003) and Dil-Ac-LDL internalization (P = 0.03) ability of GLCs were significantly reduced in women with PCOS compared to controls. Protein expression levels of endothelial markers, vascular endothelial growth factor A (VEGFA) (P = 0.004), vascular endothelial growth factor receptor 2 (VEGFR2) (P = 0.011), TEK Receptor Tyrosine Kinase (Tie-2) (P = 0.026), fibroblast growth factor receptor 1 (FGFR1) (P = 0.026) and CD31 (P = 0.035) and transcript levels of angiogenic genes VEGFA (P = 0.042), hypoxia inducing factor 1A (HIF1A) (P = 0.025), FGF2 (P = 0.038), angiopoietin 1 (ANGPT1) (P = 0.028), heparin sulfate proteoglycan 2 (HSPG2) (P = 0.016), ADAM metallopeptidase with thrombospondin type1 motif, 1 (ADAMTS1) (P = 0.027) and fibronectin 1 (FN1) (P = 0.016) were found to be low in GLCs of PCOS compared to controls. Thus, the findings of this study indicate that endothelial cell-like characteristics of GLCs were significantly decreased in PCOS. Furthermore, transcript levels of VEGFA (r = 0.46, P = 0.009), ADAMTS1 (r = 0.55, P = 0.001), FGF2 (r = 0.42, P = 0.022) and ANGPT2 (r = 0.47, P = 0.008) showed a positive correlation with oocyte fertilization rate. LIMITATIONS, REASONS FOR CAUTION The vasculature formation in CL is not possible to study in women, but we explored the angiogenic characteristics of FF and GLC obtained from women with PCOS to speculate any vascularization defect of CL in these women. The FF and GLCs were obtained from the stimulated cycle during oocyte retrieval, which may not exactly mimic the in-vivo condition. The small sample size is another limitation of this study. Larger sample size and support by color Doppler studies on CL blood flow would help to strengthen our findings. WIDER IMPLICATIONS OF THE FINDINGS Our findings suggest that the altered angiogenic potential of FF and GLCs may affect vasculature development required for CL formation and function in PCOS. These findings pave the way to devise therapeutic strategies to support angiogenesis process in follicle of women with PCOS, which may improve CL insufficiency, progesterone levels and prevent frequent miscarriages in these women. Furthermore, our study also hypothesizes that the vascularization around the ovarian follicles is also compromised which may lead to the growth arrest of the follicles in PCOS, however, this needs thorough investigations. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by Grant BT/PR16524/MED/97/346/2016 from the Department of Biotechnology, Government of India. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER N/A

scholarly journals Pro-Angiogenic Effects of Resveratrol in Brain Endothelial Cells: Nitric Oxide-Mediated Regulation of Vascular Endothelial Growth Factor and Metalloproteinases

2012 ◽  
Vol 32 (5) ◽  
pp. 884-895 ◽  
Author(s):  
Fabricio Simão ◽  
Aline S Pagnussat ◽  
Ji Hae Seo ◽  
Deepti Navaratna ◽  
Wendy Leung ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Tube Formation ◽  
Mitogen Activated Protein Kinase ◽  
Vascular Endothelial ◽  
Cerebral Endothelial Cells ◽  
Endothelial Growth Factor

Resveratrol may be a powerful way of protecting the brain against a wide variety of stress and injury. Recently, it has been proposed that resveratrol not only reduces brain injury but also promotes recovery after stroke. But the underlying mechanisms are unclear. Here, we tested the hypothesis that resveratrol promotes angiogenesis in cerebral endothelial cells and dissected the signaling pathways involved. Treatment of cerebral endothelial cells with resveratrol promoted proliferation, migration, and tube formation in Matrigel assays. Consistent with these pro-angiogenic responses, resveratrol altered endothelial morphology resulting in cytoskeletal rearrangements of β-catenin and VE-cadherin. These effects of resveratrol were accompanied by activation of phosphoinositide 3 kinase (PI3-K)/Akt and Mitogen-Activated Protein Kinase (MAPK)/ERK signaling pathways that led to endothelial nitric oxide synthase upregulation and increased nitric oxide (NO) levels. Subsequently, elevated NO signaling increased vascular endothelial growth factor and matrix metalloproteinase levels. Sequential blockade of these signaling steps prevented resveratrol-induced angiogenesis in cerebral endothelial cells. These findings provide a mechanistic basis for the potential use of resveratrol as a candidate therapy to promote angiogenesis and neurovascular recovery after stroke.

Matrix stiffness primes lymphatic tube formation directed by vascular endothelial growth factor‐C

2021 ◽  
Vol 35 (5) ◽  
Author(s):  
Laura Alderfer ◽  
Elizabeth Russo ◽  
Adriana Archilla ◽  
Brian Coe ◽  
Donny Hanjaya‐Putra
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tube Formation ◽  
Vascular Endothelial ◽  
Matrix Stiffness ◽  
Factor C ◽  
Endothelial Growth Factor

Glipizide Combined with ANP Suppresses Breast Cancer Growth and Metastasis by Inhibiting Angiogenesis through VEGF/VEGFR2 Signaling

2021 ◽  
Vol 21 ◽  
Author(s):  
Guanquan Mao ◽  
Shuting Zheng ◽  
Jinlian Li ◽  
Xiaohua Liu ◽  
Qin Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Natriuretic Peptide ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Cancer Growth ◽  
Vascular Endothelial ◽  
Breast Cancer Growth ◽  
Endothelial Growth Factor

Background: Breast cancer is one of the most common cancers worldwide among women, and angiogenesis has an important effect on its growth and metastasis. Glipizide, which is a widely used drug for type 2 diabetes mellitus, has been reported to inhibit tumor growth and metastasis by upregulating the expression of natriuretic peptide receptor A (NPRA). Atrial natriuretic peptide (ANP), the receptor of NPRA, plays an important role in angiogenesis. The purpose of this study was to explore the effect of glipizide combined with ANP on breast cancer growth and metastasis. Methods: To investigate the effect of glipizide combined with ANP on breast cancer, glipizide, ANP or glipizide combined with ANP was intraperitoneally injected into MMTV-PyMT mice. To explore whether the anticancer efficacy of glipizide combined with ANP was correlated with angiogenesis, a tube formation assay was performed. Results: Glipizide combined with ANP was found to inhibit breast cancer growth and metastasis in MMTV-PyMT mice, which spontaneously develop breast cancer. Furthermore, the inhibitory effect of ANP combined with glipizide was better than that of glipizide alone. ANP combined with glipizide significantly inhibited tube formation of human umbilical vein endothelial cells (HUVECs) by suppressing vascular endothelial growth factor (VEGF)/VEGFR2 (vascular endothelial growth factor receptor 2) signaling. Conclusions: These results demonstrate that glipizide combined with ANP has a greater potential than glipizide alone to be repurposed as effective agents for the treatment of breast cancer by targeting tumor-induced angiogenesis.

MicroRNA-34a attenuates VEGF-mediated retinal angiogenesis via targeting Notch1

2019 ◽  
Vol 97 (4) ◽  
pp. 423-430 ◽  
Author(s):  
Shaoyang Shi ◽  
Yong Jin ◽  
Haishan Song ◽  
Xiaolong Chen
Keyword(s):  
Vision Loss ◽  
Tube Formation ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Matrix Metalloproteinase 2 ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Oxygen Induced Retinopathy ◽  
Gene Assay ◽  
Retinal Angiogenesis ◽  
Endothelial Growth Factor

Pathological angiogenesis in the retina is one of the main ocular diseases closely associated with vision loss. This work investigated the roles of microRNA-34a (miR-34a) and its potential target Notch1, in retinal angiogenesis. For this we used oxygen-induced retinopathy (OIR) rats and human retinal microvascular endothelial cells (HRMECs) stimulated with vascular endothelial growth factor (VEGF). We performed hematoxylin–eosin staining, Western blot for VEGF, and immunofluorescence staining for CD31 to verify the establishment of our OIR model. We observed down-regulation of miR-34a, and up-regulation of Notch1 and Hey1 in retinas from OIR rats. We found similar results with the VEGF-stimulated HRMECs. By performing MTT assay, cell scratch assay, tube formation assay, and by detecting the expression of matrix-metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitors of metalloproteinases-1 (TIMP-1), and TIMP-2, we found that transfection of miR-34a ameliorated VEGF-mediated angiogenesis of HRMECs. We further observed that siRNA-induced gene silencing of Notch1 prevented VEGF-induced angiogenesis via regulating cell proliferation, cell migration, and tube formation of HRMECs. Additionally, activation of Notch1 by transfection of Notch1 plasmid attenuated the inhibitory effects of miR-34a on tube formation, in the present of VEGF. Results from our dual-luciferase reporter gene assay suggested that miR-34a targets Notch1. In summary, our data demonstrate that miR-34a attenuates retinal angiogenesis via targeting Notch1.

Knockdown of Nrf2 inhibits angiogenesis by downregulating VEGF expression through PI3K/Akt signaling pathway in cerebral microvascular endothelial cells under hypoxic conditions

2018 ◽  
Vol 96 (4) ◽  
pp. 475-482 ◽  
Author(s):  
Yujing Huang ◽  
Ying Mao ◽  
Huiying Li ◽  
Guangxun Shen ◽  
Guangxian Nan
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Ischemic Stroke ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Tube Formation ◽  
Vascular Endothelial ◽  
Akt Signaling Pathway ◽  
Microvascular Endothelial ◽  
Endothelial Growth Factor

Ischemic stroke is a major cerebrovascular disease resulting from a transient or permanent local reduction of cerebral blood flow. Angiogenesis plays an important role in cerebral microvascular repair after ischemic stroke. This study aimed at investigating the effect of NF-E2-related factor 2 (Nrf2) on the angiogenesis of mouse cerebral microvascular endothelial bEnd.3 cells in a hypoxic environment. We found that Nrf2 expression was temporarily increased in hypoxia-induced bEnd.3 cells. Knockdown of Nrf2 inhibited the proliferation, migration, as well as tube formation in hypoxia-induced bEnd.3 cells. Meanwhile, vascular endothelial growth factor and PI3K/Akt signaling pathways were identified to be regulated by Nrf2 in hypoxia-induced bEnd.3 cells. It was found that silencing of Nrf2 downregulated the expression levels of NAD(P)H:quinine oxidoreductase-1, vascular endothelial growth factor, p-Akt, and heme oxygenase-1 in hypoxia-induced bEnd.3 cells. Data suggested that hypoxia induced the transient increase of Nrf2, which plays a key role in the angiogenesis of cerebral microangiogenesis, and that Nrf2 regulates the proliferation, migration, as well as tube formation likely through PI3K/Akt signaling pathway in hypoxia-induced bEnd.3 cells. Our study provides proof of concept for the modulation of Nrf2, so as to tilt the balance toward angiogenesis, representing a therapeutic strategy for hypoxia or ischemia disorders such as stroke.

Expression of Vascular Endothelial Growth Factor, Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 in Polycystic Ovarian Syndrome Rats and Its Implication

2021 ◽  
Vol 11 (5) ◽  
pp. 841-846
Author(s):  
Wei Li ◽  
Yufang Zhang ◽  
Fuping Li ◽  
Yufen Shi ◽  
Yan Wang
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Matrix Metalloproteinase ◽  
Polycystic Ovary ◽  
Ovarian Tissue ◽  
Matrix Metalloproteinase 2 ◽  
Control Group ◽  
Vaginal Smear ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Polycystic ovary syndrome (PCOS) is a female endocrine disorder and frequently leads to infertility. Vascular endothelial growth factor (VEGF) has crucial roles and matrix metalloproteinase (MMPs) is correlated with cell migration. Both of them are involved in the occurrence and progression of PCOS. This study established a rat PCOS model using letrozole to measure the expression of VEGF, MMP-2 and MMP-9 (MMP-2/9), to analyze its correlation with PCOS. Letrozole was applied by gavage to establish rat PCOS model. General condition and ovarian tissue morphology were observed under a light field microscope. ELISA and immunohistochemistry (IHC) were used to detect serum or tissue expression of VEGF, MMP-2/9. Estrous cycle of rats was disrupted after 12 d for using letrozole. Vaginal smear showed abundant leukocytes with sparse keratinocytes. Ovary showed whitening and increased volume, with early phase small follicles plus lower granular cells or corpus luteum. Compared to control group, experimental group had significantly higher VEGF, MMP-2/9 (P < 0.05), which were higher in antral follicles than those in preantral follicle with higher expressions than primordial follicle (P < 0.05). In conclusion, VEGF, MMP-2/9 are abundantly expressed in both serum and tissues of PCOS rats.

scholarly journals Defining an Upstream VEGF (Vascular Endothelial Growth Factor) Priming Signature for Downstream Factor-Induced Endothelial Cell-Pericyte Tube Network Coassembly

2020 ◽  
Vol 40 (12) ◽  
pp. 2891-2909
Author(s):  
Stephanie L.K. Bowers ◽  
Scott S. Kemp ◽  
Kalia N. Aguera ◽  
Gretchen M. Koller ◽  
Joshua C. Forgy ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Protein Kinase ◽  
Rho Kinase ◽  
Tube Formation ◽  
Vascular Endothelial ◽  
Heparin Binding ◽  
Il Interleukin ◽  
Endothelial Growth Factor

Objective: In this work, we have sought to define growth factor requirements and the signaling basis for different stages of human vascular morphogenesis and maturation. Approach and Results: Using a serum-free model of endothelial cell (EC) tube morphogenesis in 3-dimensional collagen matrices that depends on a 5 growth factor combination, SCF (stem cell factor), IL (interleukin)-3, SDF (stromal-derived factor)-1α, FGF (fibroblast growth factor)-2, and insulin (factors), we demonstrate that VEGF (vascular endothelial growth factor) pretreatment of ECs for 8 hours (ie, VEGF priming) leads to marked increases in the EC response to the factors which includes; EC tip cells, EC tubulogenesis, pericyte recruitment and proliferation, and basement membrane deposition. VEGF priming requires VEGFR2, and the effect of VEGFR2 is selective to the priming response and does not affect factor-dependent tubulogenesis in the absence of priming. Key molecule and signaling requirements for VEGF priming include RhoA, Rock1 (Rho-kinase), PKCα (protein kinase C α), and PKD2 (protein kinase D2). siRNA suppression or pharmacological blockade of these molecules and signaling pathways interfere with the ability of VEGF to act as an upstream primer of downstream factor-dependent EC tube formation as well as pericyte recruitment. VEGF priming was also associated with the formation of actin stress fibers, activation of focal adhesion components, upregulation of the EC factor receptors, c-Kit, IL-3Rα, and CXCR4 (C-X-C chemokine receptor type 4), and upregulation of EC-derived PDGF (platelet-derived growth factor)-BB, PDGF-DD, and HB-EGF (heparin-binding epidermal growth factor) which collectively affect pericyte recruitment and proliferation. Conclusions: Overall, this study defines a signaling signature for a separable upstream VEGF priming step, which can activate ECs to respond to downstream factors that are necessary to form branching tube networks with associated mural cells.

149 EXPRESSION OF ANGIOGENIC FACTORS AND THEIR MAJOR RECEPTORS IN THE SHEEP PLACENTA THROUGHOUT THE EARLY PREGNANCY

2006 ◽  
Vol 18 (2) ◽  
pp. 182
Author(s):  
P. P. Borowicz ◽  
D. A. Redmer ◽  
A. T. Grazul-Bilska ◽  
G. Ptak ◽  
P. Loi ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Growth Factor Receptor ◽  
Angiogenic Factors ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
Fibroblast Growth ◽  
Mrna Concentration ◽  
Endothelial Growth Factor

Embryonic losses are high in mammals, with more than 30% of fertilized eggs not resulting in an offspring. The development of the placenta is critical for normal fetal growth and development as it provides for exchange of respiratory gases, nutrients, and wastes between the fetal and maternal systems. Placental vascular development determines the rate of placental blood flow, which is a primary determinant of placental function. Recent studies suggest that vascular endothelial growth factor (VEGF), its receptors (VEGFR), along with angiopoietins (Ang-1 and Ang-2) and their common receptor Tie-2, are major placental angiogenic factors, along with fibroblast growth factor-2 (FGF-2) and its receptor (FGFR). To evaluate the patterns of placental expression of these factors during early placental development, gravid uteri were obtained from ewes (n = 6 per day) on Days 12, 18, 24, 30, and 40 of gestation (day of mating = Day 0). At slaughter the uterine and embryonic tissues were weighed and representative samples of utero-placenta (CAR - caruncle, maternal placenta; ICAR - intracarunclar, endometrium; FM, fetal membranes) were snap frozen on dry ice and analyzed for relative mRNA levels by real-time RT-PCR (ABI Prism 7000, Sequence Detection System, Applied Biosystems, Monza, Italy) of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-1 (VEGFR-1), vascular endothelial growth factor receptor-2 (VEGFR-2), angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), receptor for both angiopoietins (Tie-2), fibroblast growth factor-2 (FGF-2), and fibroblast growth factor receptor (FGFR). The data were analyzed by nonlinear procedures using proc reg of SAS (SAS Institute, Inc., Cary, NC, USA). In CAR, the data showed the exponential increase from Days 12 to 40 in mRNA expression for VEGFR-1 (P < 0.0004; 0.04398e0.08794�day), VEGFR-2 (P < 0.01; 0.119208e0.06537�day), Ang-1 (P < 0.005; 0.00488e0.10881�day), Ang-2 (P < 0.0001; 0.01591e0.07864�day), Tie-2 (P < 0.03; 0.00488e0.06852�day), and FGFR (P < 0.08; 0.24577e0.04721�day). In the CAR, we also observed an exponential decrease in mRNA concentration for VEGF (P < 0.05; 28.193e-1.0719�day). In ICAR, we observed an exponential increase in mRNA concentration for VEGF (P < 0.05; 1.11685e0.06865�day), VEGFR-1 (P < 0.07; 0.09853e0.0383�day), Ang-1 (P < 0.09; 0.009318e0.05711�day), and Ang-2 (P < 0.004; 0.012647e0.09973�day). For FM, no changes in mRNA levels were observed from Days 12 to 40, but levels of all mRNAs were similar to those in CAR and ICAR. Based on the patterns of mRNA expression, these data indicate that these angiogenic factors may play an important role in early placental angiogenesis in sheep. This work was supported by NIH grant HL64141 to LPR and DAR.

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