Dissertations / Theses on the topic 'Angiopoietin'
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Tausch, Kathrin. "Expression von Angiopoietin-1 und Angiopoietin-2 im Endometrium und in Endometriosegewebe." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=971973113.
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Neuschl, Elvira. "Einfluss von Angiopoietin-1 und Angiopoietin-2 auf die Angiogenese im Ratten-Gliommodell." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=979987113.
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Drenkhahn, Merle. "Expression von Angiopoietin-1 und Angiopoietin-2 im ektopen Endometrium auf der Chorioallantoismembran." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=976803968.
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Gardizi, Masyar [Verfasser]. "Angiopoietin-1 und Angiopoietin-2 als Serummarker für das Maligne Melanom / Masyar Gardizi." Köln : Deutsche Zentralbibliothek für Medizin, 2013. http://d-nb.info/1046472232/34.
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Moss, Andrew James. "Engineering novel angiopoietin receptor ligands." Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/27654.
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Angiopoietin-1 is a multimeric glycoprotein which signals through the vascular endothelial Tie2 receptor to protect against inflammation and leakage, an effect antagonised by the selectively upregulated antagonist angiopoietin-2. In many pathologies this destabilisation by angiopoietin-2 is excessive or inappropriate, and here angiopoietin-1 has a promising role in therapeutic application. However angiopoietin-1 is difficult to purify and administer, its large multimeric structure rendering it prone to aggregation and insolubility. In this work the abilities of two small heptameric Tie2 binding peptides, VTSRGNV and NLLMAAS, multimerised using the established oligomeric scaffold cartilage oligomeric matrix protein (COMP), to bind and activate Tie2 were investigated. cDNAs for synthetic ligands were created by PCR, and protein synthesis was carried out in mammalian and bacterial expression systems. Ligands were expressed as stable, soluble pentamers and tetramers which showed similar abilities to bind Tie2 in vitro. Both ligands activated Tie2 similarly in Eahy926 and HUVEC endothelial cells. Both ligands were also able to activate two important downstream signalling mediators of Tie2 in HUVECs, namely Akt and ERK, in a dose-dependent fashion. However, the kinetics of ERK appeared different between the two ligands, implying possible differences in signalling of the two ligands through Tie2. This work is proof of principle and is among the first work to demonstrate that Tie2 binding elements other than the ang1 FRD can be used to activate Tie2. Additionally, kinetics work suggests that the two ligands, presumed to bind to different areas on Tie2, might induce slightly different patterns of receptor activation.
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Alves, Brunna Eulálio 1979. "Avaliação de moduladores do aumento da permeabilidade microvascular e sua correlação com a evolução clínica na sepse em pacientes onco-hematológicos neutropênicos febris." [s.n.], 2011. http://repositorio.unicamp.br/jspui/handle/REPOSIP/309168.
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Orientador: Erich Vinicius de PaulaTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-18T13:46:04Z (GMT). No. of bitstreams: 1 Alves_BrunnaEulalio_D.pdf: 4762678 bytes, checksum: 34eea414d90830a52ed9c9b044538888 (MD5) Previous issue date: 2011
Resumo: Pacientes portadores de neoplasia hematológica e neutropenia febril representam um grupo de risco elevado de sepse e choque séptico. Nas últimas décadas, estratégias terapêuticas alvo-específicas para a sepse não modificaram de forma significativa a sobrevida dos pacientes e o tratamento permanece baseado em antibioticoterapia e cuidados de suporte, com altas taxas de mortalidade. A quebra da barreira endotelial é um evento fundamental na fisiopatologia do choque séptico e a compreensão dos mecanismos envolvidos neste evento tem o potencial de auxiliar na identificação de novos biomarcadores de gravidade e de novos alvos terapêuticos para estes pacientes. Estudos recentes demonstraram a participação do fator de crescimento do endotélio vascular (VEGF-A), do seu receptor solúvel (sFlt-1) e das angiopoietinas 1 e 2, proteínas envolvidas na angiogênese e na regulação da integridade da barreira endotelial na fisiopatogenia do choque séptico em pacientes não oncológicos internados em unidade de terapia intensiva. Neste trabalho, avaliamos prospectivamente a cinética do VEGF-A, do sFlt-1 e das angiopoietinas 1 e 2 durante as 48 horas inicias da neutropenia febril em 41 pacientes portadores de neoplasia hematológica submetidos a quimioterapia intensiva ou a regime de condicionamento para transplante de células progenitoras hematopoiéticas, através da dosagem dos mesmos por ensaio imuno-enzimático. Exploramos também a associação dos níveis séricos destes biomarcadores com a gravidade da sepse através da correlação com o MASCC, um índice desenvolvido para identificar pacientes com neutropenia febril de baixo risco, e com o SOFA, um escore de avaliação de disfunção orgânica em pacientes com sepse, ambos amplamente aceitos. A evolução para choque séptico foi associada a níveis significativamente maiores de VEGF-A, sFlt-1 e angiopoietina-2 48 horas após o início da neutropenia febril quando comparado aos valores em pacientes com sepse não complicada e a estimativa da acurácia diagnóstica sugere a capacidade de discriminar os pacientes que evoluíram com choque séptico. Estes biomarcadores também apresentaram correlação com os escores gravidade, sugerindo a relevância biológica da associação. Em conclusão, nossos achados sugerem que a avaliação destes biomarcadores em pacientes com neutropenia febril deve ser avaliada em estudos com maior número de pacientes, quanto ao seu potencial de incorporação na prática clínica. Além disso, os resultados reforçam o potencial terapêutico da intervenção nestas vias para o tratamento da sepse
Abstract: Patients with hematologic malignancy and neutropenia represent a group at high risk of sepsis and septic shock. In recent decades, target-specific therapeutic strategies for sepsis did not change significantly the survival of patients and treatment is still based on antibiotic therapy and supportive care, with high mortality rates. The breakdown of the endothelial barrier is a key event in the pathophysiology of septic shock and understanding of the mechanisms involved in this event has the potential to assist in the identification of new biomarkers and severity of new therapeutic targets for these patients. Recent studies have demonstrated the involvement of endothelial growth factor (VEGF-A), its soluble receptor (sFlt-1) and angiopoietins 1 and 2, proteins involved in angiogenesis and in regulation of endothelial barrier integrity in the pathogenesis of shock septic patients without cancer admitted to the intensive care unit. In this study, we prospectively evaluated the kinetics of VEGF-A, sFlt-1 and angiopoietins 1 and 2 during the initial 48 hours of febrile neutropenia in 41 patients with hematological malignancy undergoing intensive chemotherapy or conditioning regimen for stem cell transplantation hematopoietic cells by the same dosage by enzyme immunoassay. We also explored the association of serum levels of these biomarkers with the severity of sepsis through correlation with the MASCC, an index developed to identify patients with febrile neutropenia at low risk, and the SOFA score for assessment of organ dysfunction in patients with sepsis, both widely accepted. Progression to septic shock was associated with significantly higher levels of VEGF-A, sFlt-1 and angiopoietin-2 48 hours after the onset of febrile neutropenia when compared to values in patients with uncomplicated sepsis and the estimation of diagnostic accuracy suggests the ability to discriminate among patients who developed septic shock. These biomarkers also correlated with the severity scores, suggesting the biological relevance of the association
Doutorado
Clinica Medica
Doutor em Clínica Médica
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Ward, Emma Gwenllian. "Characterisation of the human angiopoietin genes." Thesis, University of Leeds, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.413277.
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Pietilä, R. (Riikka). "Angiopoietin 1 and 2-regulated Tie2 receptor translocation in endothelial cells and investigation of Angiopoietin-2 splice variant 443." Doctoral thesis, Oulun yliopisto, 2015. http://urn.fi/urn:isbn:9789526207971.
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Abstract Angiopoietins 1 and 2 (Ang1 and Ang2) are the ligands of the Angiopoietin/Tie signalling system, which is a binary pathway offering mechanisms for healthy vessels to reach and maintain their quiescence but also to rapidly respond to activating stimuli leading to a remodelling of endothelium. The latter is linked to disease settings such as inflammation and cancer where endothelial cell (EC) integrity is compromised and is often related to an increase in Ang2 expression. This study focused on the mechanisms enabling Ang1 to mediate both EC stability and migration and molecular and cellular determinants for ligand-specific functions of Ang2 and its isoform Ang2443. The findings revealed that Ang1 induces differential signalling depending on whether it anchors and activates Tie2 in cell-cell junctions in quiescent ECs, or in cell-matrix contacts in mobile ECs, thus leading to cellular phenotypes characteristic of resting and mobile ECs, respectively. In the second part of the thesis Ang2-Tie2 specific cell-extracellular matrix (ECM) contact sites were studied. Formation of Ang2/Tie2 EC-ECM contact sites was dependent on the collagen I and IV matrices, low Ang2 oligomerization state, α2β1-integrins, and intact microtubules. In the third part of the thesis the comparison of Ang2 mRNA splice variant Ang2443 with full length Ang2 (Ang2FL) revealed both redundant and ligand form–specific effects, expression of Ang2443443 increased the amount of monomeric ligand forms due to proteolytic processing and promoted transendothelial migration of cancer cells in vitro. On the other hand, both Ang2443 and Ang2FL were stored in endothelial Weibel-Palade bodies (WPBs), similarly induced Ang2-specific Tie2 cellular redistribution, and were mostly comparable in developmental angio- and lymphangiogenesisTiivistelmä Angiopoietiinit 1 ja 2 (Ang1 ja Ang2) ovat Ang/Tie signalointireitin kasvutekijöitä. Ang1 kasvutekijää tarvitaan sydämen ja verisuoniston sikiöaikaiseen kehittymiseen, se vähentää Tie2 reseptorin kautta verisuonten läpäisevyyttä, mutta edistää myös yksittäisten endoteelisolujen liikkumista. Saman Tie2 signalointireitin toisen kasvutekijän Ang2:n ilmeneminen johtaa verisuonten läpäisevyyden kasvuun tulehduksessa, uusien verisuonten muodostumiseen syöpäkasvaimissa ja syöpäsolujen leviämiseen elimistössä. Väitöskirjatutkimuksessa selvitettiin niitä solutason mekanismeja, joilla Ang1 kykenee välittämään sekä endoteelisolujen tiiviyttä että liikkumista. Lisäksi tutkittiin niitä molekyyli- ja solutason mekanismeja, joilla Ang2 ja sen isomuoto Ang2443 välittävät kasvutekijäspesifisiä vaikutuksiaan. Väitöskirjassa osoitettiin että Tie2 reseptori paikantuu verisuonten endoteelisoluissa Ang1 sitoutumisen seurauksena joko solu-soluliitoksiin, tai yksittäisissä endoteelisoluissa solu-soluväliaine rajapinnalle. Tie2:n siirtyminen solu-soluliitoksiin aktivoi soluissa signalointireittejä, jotka ovat tyypillisiä normaaleille tiiviille verisuonille ja solu-soluväliaineliitoksissa liikkuville endoteelisoluille tyypillisiä piirteitä. Väitöskirjatyön toisessa osassa tutkittiin Ang2:lle ominaisia vaikutuksia ja Ang2-Tie2 kompleksin paikantumista erityisiin solu-soluväliaineliitoksiin. Tämä oli riippuvaista Ang2:n oligomerisaatiosta, kollageenisoluväliaineesta, α2β1-integriinistä ja normaalista mikrotubulusverkostosta. Väitöskirjatyön kolmannessa osassa osoitettiin että Ang2443 isomuodolla on sekä yhteisiä että isomuotospesifisiä piirteitä verrattuna kokopitkään Ang2:een (Ang2FL). Liukoinen Ang2443, mutta ei Ang2FL, esiintyi yleisesti monomeerisenä ligandimuotona proteiinin multimerisaatio-osan pilkkomisen seurauksena. Ang2443 lisäsi myös syöpäsolujen liikkumista endoteelisolujen läpi. Toisaalta sekä Ang2443 että Ang2FL varastoitiin endoteelisoluissa Weibel-Palade varastokappaleisin, ne välittivät samanlaista Tie2 reseptorin paikantumista endoteelisoluissa ja toimivat pääsääntöisesti samanlaisina kasvutekijöinä veri- ja imusuonten kehityksen aikana hiiressä
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Li, Shihhui. "Angiopoietin-like protein 4 in bovine physiology." Thesis, Kansas State University, 2011. http://hdl.handle.net/2097/13107.
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Master of ScienceDepartment of Animal Sciences and Industry
Barry Bradford
Angiopoietin-like protein 4 (ANGPTL4) is a 55-kDa secreted glycoprotein which is an important factor for regulation of energy and lipid metabolism. Plasma ANGPTL4 has the ability to inhibit lipoprotein lipase (LPL) function by preventing it from catalyzing hydrolysis of lipoprotein triglyceride, which contributes to ANGPTL4’s ability to decrease fat storage. Furthermore, research in mice suggests that gut microbes suppress gastrointestinal ANGPTL4 production, and that decreased plasma ANGPTL4 concentrations promote fat storage. In our previous work, we found that bovine ruminal epithelial cells expressed ANGPTL4 to a greater extent than liver hepatocytes, which are usually considered the predominant source of circulating ANGPTL4. Therefore, 3 studies were conducted to evaluate the hypothesis that ruminal expression and plasma concentrations of ANGPTL4 could be influenced by alterations in ruminal fermentation. The first and second studies utilized dietary treatments intended to alter ruminal fermentability. Diets with relatively low or high forage content were fed to 12 non-lactating dairy cows (study 1) and 8 beef cattle (study 2) prior to collection of ruminal fluid and ruminal tissue samples. The results suggested that increasing the dietary concentrate decreased ruminal expression of ANGPTL4 but did not significantly alter plasma ANGPTL4 concentrations. The third study was designed to assess whether effects of diet fermentability on ruminal ANGPTL4 synthesis are mediated by changes in volatile fatty acid concentrations. In this study, 6 lactating cows were infused with acetate, propionate, or butyrate in a Latin square design. Results showed that ANGPTL4 expression was not significantly altered by volatile fatty acid infusions, but that expression was correlated with ruminal pH and total volatile fatty acid concentration. The mechanism by which ANGPTL4 regulates intracellular lipid metabolism also remains unclear. Although ANGPTL4 is known to associate with β1 and β5 integrins, it is unknown if these extracellular matrix proteins mediate the effects of ANGPTL4 in adipose tissue or muscle. The objective of the last experiment was to detect the ANGPTL4 receptor or mediator in muscle satellite cells and adipose tissue. We successfully expressed recombinant bovine ANGPTL4 with a cell free glycoprotein synthesis system. However, we did not detect the ANGPTL4–receptor complex following exposure to bovine adipose tissue explants or cultured bovine muscle satellite cells. Overall, these research projects determined that the ruminal ANGPTL4 production is influenced by fermentation, but it remains unclear whether fermentation products or direct host/microbe interactions are responsible. Finally, it will be important to identify the ANGPTL4 receptor or mediator to better understand the downstream regulatory mechanisms involved in mediating the metabolic effects of ANGPTL4.
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Long, David Andrew. "Angiopoietin growth factors in models of kidney disease." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401031.
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Alawo, Deborah O. A. "Computational modelling of the angiopoietin and Tie interactions." Thesis, University of Leicester, 2014. http://hdl.handle.net/2381/39222.
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Angiopoietins have been shown to regulate the vascular states of development and quiescence. Activation of this signalling pathway through their receptor tyrosine kinase, Tie2, is involved in angiogenesis and vascular protection. Regulation of this pathway is under tight control and has many complex factors which regulate its activation, defects in which cause many pathological conditions such as; vascular disease, sepsis and cancer. There are several factors which are integrated to control the Tie2 signalling pathway at the level of the receptor and these mechanisms are poorly understood. Computational and mathematical modelling can be used to understand the regulation of this pathway. The aim of this project was to construct a quantitative model of the angiopoietin and Tie interactions at the endothelial cell surface. A schematic representation of the interactions was produced in the CellDesigner modelling program. Ordinary differential equations were used to describe the system and change of states over time. Parameters required for the simulation of the model were identified and most were obtained from the literature, while others were quantified through experiments. The model was converted for use in MATLAB to simulate the angiopoietin time-courses and concentration-dependent studies. Quantitative Western blotting was used to measure the relative levels of receptor activation in endothelial cells stimulated with angiopoietin(s). Subsequently simulation results were compared to experimental data to validate the model. In summary this project has established a model similar to physiological conditions which is valid for Ang1 and potentially for Ang2 interactions. This simplified model of Ang1 and Ang2 interactions with Tie2 on the endothelial cell surface provides a foundation on which further analysis, and additional receptor modelling can be performed and expanded. The model can also be used to test hypotheses, generate new predictions, and identify new therapeutic targets for many diseases.
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Todd, Alexandra Frances. "The role of angiopoietin-2 in vascular calcification." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10044744/.
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Cardiovascular disease (CVD) is a leading cause of mortality in paediatric patients with chronic kidney disease (CKD), particularly in those undergoing dialysis. One of the earliest events in CVD is endothelial damage, which may result from changes in levels of vascular growth factors that control blood vessel function and stability. Markers of endothelial dysfunction and vascular calcification are observed during CKD, and are documented as early as the first decade of life. Previous research indicates that growth factors controlling blood vessel function and stability are altered in CKD patients; circulating levels of the pro-inflammatory/anti-angiogenic molecule angiopoietin-2 (Angpt2) are notably increased in children on dialysis and correlate with surrogate markers of vascular calcification. I therefore hypothesise that Angpt2 may promote medial calcification in CKD. Through in vitro studies using intact vessel rings and explanted vascular smooth muscle cells (VSMCs) from paediatric pre-dialysis and dialysis patients, I have shown that addition of exogenous Angpt2 in a pro-calcaemic environment (medium supplemented with 2.7 mM calcium, and 2.0 mM phosphate) increases calcium deposition within vessels from dialysis patients, but has no effect on control or predialysis vessels. In endothelial cells, Angpt2 acts through the receptor tyrosine kinase with immunoglobulin-like and EGF-like domains-2 (Tie2); this receptor was detected through immunofluorescence in the media layer of the intact vessels and by protein and RNA analyses of explanted VSMCs. The calcifying effect of Angpt2 in VSMCs could be blocked by downregulating Tie2 expression by small interfering ribonucleic acid (siRNA), but was not prevented by addition of the Angpt2 antagonist, vascular stabiliser and anti-inflammatory molecule, Angpt1. Vascular calcification is driven through several pathophysiological mechanisms including osteogenic gene expression, apoptosis and vesicle release; these have been investigated in both vascular rings and explanted VSMCs. While the full mechanism has yet to be elucidated, this thesis provides evidence to suggest that manipulation of Tie2 and angiopoietin pathways may have potential to decrease the rate of vascular calcification in patients with CKD.
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Hall, Kelly L. "Angiopoietin-2 overexpression promotes hematogenous metastasis in breast cancer /." Available to subscribers only, 2009. http://proquest.umi.com/pqdweb?did=1967985931&sid=2&Fmt=2&clientId=1509&RQT=309&VName=PQD.
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Thesis (M.S.)--Southern Illinois University Carbondale, 2009."Department of Medical Microbiology, Immunology, and Cell Biology." Includes bibliographical references (p. 97-133). Also available online.
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Abdel, Malak Nelly. "Signalling and mediators of Angiopoietin-1 in endothelial cells." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115914.
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Angiopoietin-1 (Ang-1), the main ligand for the endothelial cell (EC)-selective Tie-2 receptors, promotes survival, proliferation, migration and differentiation of these cells. Despite its importance in various aspects of vascular biology, the mechanisms of action of the Ang-1/Tie-2 receptor pathway have not been fully explored.To identify the downstream modulators of Ang-1, we evaluated changes in the transcriptome of human umbilical vein endothelial cells (HUVECs) treated with Ang-1 protein for four hours by employing the oligonucleotide rnicroarray technology. Eighty-six genes were significantly upregulated by this treatment and forty-nine genes were significantly downregulated. These genes are involved in the regulation of cell cycle, proliferation, apoptosis, transcription and differentiation. Furthermore, we found that the Erk1/2, PI3-Kinase and mTOR pathways are implicated in promoting gene expression in HUVECs in response to Ang-1. Analysis of the microarray data employing the Ingenuity Pathways analysis software to place the regulated genes in the context of biological networks revealed several highly connected nodes including the chemokine Interleukin-8 (IL-8) and the transcription factor Early growth response-1 (Egr-1). Due to the importance of these genes in promoting angiogenesis, we decided to evaluate their roles in Ang-1/Tie-2 receptor signaling and biological effects.
Ang-1 induced IL-8 expression in a time- and dose-dependent manner in ECs through both transcriptional and post-transcriptional mechanisms. To study the functional role of Ang-1-induced IL-8, we generated HUVECs that overexpress Ang-1. In these cells, neutralizing IL-8 significantly reduced EC proliferation and migration. IL-8 promoter activity experiments and gel shift assays revealed the involvement of the transcription factor AP-1 in Ang-1-induced IL-8. Ang-1 stimulated the phosphorylation of c-Jun through activation of Erk1/2, JNK and PI-3 kinase pathways. Similarly, Ang-1 provoked the expression and DNA binding of Egr-1 in HUVECs. Employing siRNA and DNAzyme to specifically knock-down Egr-1, we found that Ang-1-induced Egr-1 also promotes EC proliferation and migration.
We conclude that Ang-1 provokes a coordinated response intended to promote EC survival, proliferation, and angiogenesis and to inhibit EC apoptosis. Ang-1 induces EC proliferation and migration in part through the secretion of the soluble mediator Interleukin-8 and through induction of the transcription factor Egr-1.
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Tressel, Sarah Lynne. "Role of shear stress in angiopoietin-2-dependent neovascularization:." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/22646.
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Thesis (Ph. D.)--Biomedical Engineering, Georgia Institute of Technology, 2008.Committee Chair: Jo, Hanjoong; Committee Member: McIntire, Larry; Committee Member: Nie, Shuming; Committee Member: Taylor, Robert; Committee Member: Weyand, Cornelia.
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Hall, Kelly. "ANGIOPOIETIN-2 OVEREXPRESSION PROMOTES HEMATOGENOUS METASTASIS IN BREAST CANCER." OpenSIUC, 2009. https://opensiuc.lib.siu.edu/theses/154.
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Angiogenesis supports tumor growth and facilitates metastasis, the leading cause of patient mortality in breast and other types of solid tumors. Angiopoietin-2 (Ang-2) is an angiogenic factor whose overexpression is associated with increased tumor vascularity, metastasis, and decreased patient survival. We assessed the effects of Ang-2 on breast tumor vasculature by comparing vascular morphology and metastasis of orthotopically implanted metastatic breast carcinoma line MDA-MB-231 that either lacked or overexpressed Ang-2. Methods: Luciferase-tagged MDA-MB-231 breast carcinoma cells designated hAng2 were engineered to overexpress human Ang-2. The control line expressed hAng-2 in reverse orientation. Stable production of hAng-2 was confirmed by RT-PCR, qRT-PCR, Western blot, and ELISA. Functionality of recombinant hAng-2 was assessed by migration and proliferation assays. MDA-MB-231 tumors, hAng2 and control, were orthotopically implanted into female Nu/Nu and SCID mice. Metastasis to lymph node and lung were determined by measuring luciferase activity in tissue extracts. Tumor blood vessel morphology was analyzed by immunohistochemistry (IHC) using antibodies against MECA-32, smooth muscle actin (SMA-alpha), VEGFR-3 and Notch-1. Results: MDA-MB-231 hAng2 lines were stably generated to produce 0-370 ng/ml of hAng-2 while expression in control line was undetectable. Tumor-produced hAng-2 was functional as demonstrated by a dose-dependent induction of migration of lymphatic endothelial cells and mouse mesenchymal stem cells with a maximum increase of 3-fold. Overexpression of Ang-2 had no significant effect on proliferation of cultured MDA-MB-231 cells, growth rate of hAng2 tumors or blood vessel density. In contrast, we detected substantial differences in vascular morphology of Ang-2 overexpressing tumors including 1.7-fold increase in blood vascular area, 2.8-fold increase in number of vessels with open lumen, and 6-fold increase in lumens' cross-sectional area. Blood vascular pericyte coverage shown by SMA-α staining decreased (p>0.001) in hAng2 tumors, demonstrating vessel destabilization. Blood vascular invasion by tumor cells and pulmonary metastasis increased in Ang-2 overexpressing tumors by 500% and 1100%, as compared with control tumors. Blood vessels in hAng2 tumors, but not lymphatic vessels, displayed significantly upregulated Notch-1 and VEGFR-3 expression amplified by a 2.2-fold. Conclusions: These data suggest that Ang-2 increases metastasis because of suppression of pericytes' recruitment that leads to destabilization of the tumor vessels, which facilitates the entry of tumor cells into the vessels and increases metastatic spread. These effects are associated with up-regulation of Notch-1 and VEGFR-3 on tumor vasculature suggesting that signaling of these proteins underlie the morphologic changes in Ang-2 overexpressing tumors. This is consistent with prior data demonstrating up-regulation of VEGFR-3 on tumor blood vessels and association of both proteins with increased metastasis. This study demonstrates that Ang-2 plays a key role in hematogenous metastasis and suggests that Ang-2 might represent novel a target for inhibition of breast cancer metastasis.
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Chi, Xun. "Extracellular regulation of LPL activity by angiopoietin-like proteins." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/5729.
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Dyslipidemia often accompanies metabolic diseases such as obesity and type II diabetes mellitus and represents a risk factor for cardiovascular disease. Clearance of triglycerides from the plasma is mediated by lipoprotein lipase (LPL), which hydrolyzes the triglycerides in chylomicrons and VLDL, liberating fatty acids for tissue uptake. LPL functions in the capillaries of the heart, adipose tissue, and skeletal muscle where LPL is anchored to the capillary wall by its endothelial cell transporter GPIHBP1. LPL activity is regulated by several factors including three members of the angiopoietin-like (ANGPTL) family–ANGPTL3, ANGPTL4, and ANGPTL8. How these proteins interact with LPL, especially in the physiological context of LPL anchored to endothelial cells by GPIHBP1, has not been well characterized. In my studies of ANGPTL4, I found when LPL is bound to GPIHBP1, it is partially, but not completely, protected from inactivation by ANGPTL4. Inactivation of LPL by ANGPTL4 leads to the dissociation of active LPL dimers into inactive monomers and I found that these monomers have a greatly reduced affinity for GPIHBP1. ANGPTL4 can be cleaved in vivo, separating the N-terminal coiled-coil domain from the C-terminal fibrinogen like-domain. I found the N-terminal domain alone is a much more potent LPL inhibitor than the full-length protein, even though both appear to have similar binding affinities for LPL-GPIHBP1 complexes. When I investigated ANGPTL3, I found ANGPTL3 itself is not a potent inhibitor of LPL at physiological concentrations, and unlike ANGPTL4, cleavage of ANGPTL3 does not improve its ability to inhibit LPL. Instead I found that ANGPTL3 forms a complex with ANGPTL8, a complex that only forms efficiently when the two proteins are co-expressed, and that this complex allows ANGPTL3 to bind and inhibit LPL. My data provide new insights into how ANGPTL proteins regulate LPL activity and the delivery of fat to tissues.
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Golyardi, Flora. "Angiopoietin-1 signaling in endothelial cells: role of microRNAs (miRNAs)." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=123113.
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MiRNAs are relatively small (21-23 nucleotide), single-stranded, evolutionarily conserved, non coding RNA molecules that usually inhibit mRNA expression or protein translation and thereby regulate gene expression. Angiopoientin-1 (Ang-1), along with its receptors Tie-1 and Tie-2, play a major role in Angiogenesis, the sprouting of new blood vessels. We first exposed endothelial cells (ECs) to Ang-1 for 12, 24, and 48h and assessed the expression of human miRNAs using Affymatrix arrays. Our results revealed that Ang-1 exposure elicits significant changes in miRNA expression with numerous miRNA being downregulated and only few miRNAs which were upregulated. One miRNA (miR-146b-5p) was significantly upregulated in ECs exposed to 12, 24, and 48h of Ang-1. This miRNA is a well-known regulator of innate immune responses and has been described to significantly inhibit the expression of IRAK1 and TRAF6 proteins which are involved in Toll-like 4 receptor signaling. Ang-1 exposure for 12hr triggered significant rise in the expression of 9 miRNAs while exposure to Ang-1 for 24 and 48h elicited a significant increased in the expression of 8 and 15 miRNAs, respectively. Exposure to Ang-1 also triggered significant inhibition of the expression of 14, 6, and 7 miRNAs after 12, 24 and 48h of exposure, respectively. The majority of these miRNAs have not been well characterized in terms of specific molecular targets or biological responses. In our subsequent experiments, we focused our attention on the biological roles of 8 miRNAs whose expression is downregulated by Ang-1. Our hypothesis was that these miRNAs exert a strong inhibitory influence on angiogenic processes and that their downregulation is essential for the pro-angiogenic effect of Ang-1 to be expressed. We used cell counting, caspase 3/7 activity assays, scratch healing assays, Matrigel® in vitro tube formation assays and cell cycle measurements to characterize the influence of several miRNAs on cell survival, apoptosis, migration, differentiation, and cell cycle regulation. Our results revealed that miR-1468, miR-1287, and miR-1233 significantly inhibit the pro-survival influence of Ang-1 on ECs, whereas miR-103, miR-330-5p, miR-557, miR-575 and miR-668 had no significant effects. In addition, these three miRNAs significantly attenuate EC migration, EC differentiation and impaired cell cycle progression. We conclude that several anti-angiogenic miRNAs are strongly downregulated in ECs exposed to Ang-1 and that this response is designed to promote the pro-angiogenic effects of Ang-1.Les microARN (ou miARN) sont de courtes (21 à 23 nucléotides) molécules d'acide ribonucléique (ARN) à simple-brin, non codantes et évolutionairement conservées. Ces molécules servent à réguler l'expression génétique en inhibant l'expression d'ARN messagers ou la traduction de protéines. Nous avons d'abord exposé des cellules endothéliales (CE) à Angiopoeitin-1 (Ang-1) pendant 12, 24 et 48 heures pour ensuite évaluer l'expression des miARN humains avec des essais Affymatrix. Nos résultats révèlent que l'exposition à Ang-1 élicite des changements d'expression significatifs, puisque plusieurs miARN ont été diminués tandis que seulement quelques-uns ont été augmentés. L'expression de la molécule miR-146b-5p a été significativement accrue dans les CE exposées à Ang-1 pour 12, 24 et 48 heures. Ce miARN est un régulateur bien connu du système immunitaire et a été établi d'entraver l'expression des protéines IRAK1 et TRAF6 qui participent dans la signalisation du récepteur Toll-like 4 (TLR4). Le traitement avec Ang-1 de 12 heures a provoqué une augmentation signification de l'expression de 9 miARN, tandis que les traitements de 24 et 48 heures ont entrainé une hausse de l'expression de 8 et 15 miARN, respectivement. L'exposition à Ang-1 a aussi réduit l'expression de 14, 6 et 7 miARN suivant des traitements de 12, 24 et 48 heures, respectivement. La majorité de ces miARN n'ont pas encore été bien caractérisés en termes de cible moléculaires spécifiques ou de processus biologiques. Dans nos manipulations subséquentes, nous avons tourné notre attention vers les rôles biologiques de 8 espèces de miARN qui ont vu leur expression diminuée par Ang-1. Notre hypothèse était que ces miARN exercent une puissante influence inhibitoire sur les processus angiogéniques et que leur répression serait essentielle pour les effets pro-angiogéniques d'Ang-1. Nous avons compté les cellules, utilisé des essais d'activité Caspase 3/7, des tests de cicatrisation de plaie et de différenciation Matrigel, ainsi qu'effectué des mesures du cycle cellulaire pour déterminer l'influence de plusieurs miARN sur la survie des cellules, l'apoptose, la migration, la différenciation et la régulation du cycle cellulaire. Nos résultats démontrent que miR-1468 miR-1287 et miR-1233 inhibent significativement l'effet d'Ang-1 de promouvoir la survie des CE. De plus, ces 3 miARN ont significativement atténué la migration, la différenciation et la progression du cycle cellulaire des CE. Nous concluons que plusieurs miARN anti-angiogéniques sont réduits dans les CE exposés à Ang-1 et que cette réponse est conçue pour promouvoir les effets pro-angiogéniques de Ang-1.
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Ziegler, Tilman. "Mikrozirkulatorische und hämodynamische Veränderungen durch pan-endotheliale Angiopoietin-2 Überexpression." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-175915.
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Schumacher, Anne [Verfasser]. "Angiopoietin-like 4 als Mediator der reaktiven Hämatopoese / Anne Schumacher." Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2014. http://d-nb.info/1058392921/34.
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Echavarria, Raquel. "Regulation of angiogenesis, breast cancer and inflammation by angiopoietin-1." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=119607.
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Angiogenesis and inflammation are hallmarks of several pathologies including breast cancer. The angiopoietins and Tie receptors have emerge as alternative targets for therapeutical intervention due to their function as essential regulators of angiogenesis, vascular homeostasis and inflammation. Angiopoietin-1 (Ang-1), the main agonist of Tie-2 receptors, promotes vessel growth, inhibits inflammation and maintains vessel stability. Although important advances have been made in understanding the functions of Ang-1 in the vasculature the intracellular signaling pathways activated by Ang-1, as well as its role in breast cancer and inflammation, remain largely unexplored. Using human umbilical vein endothelial cells (HUVECs), we identified dual-specificity phosphatases (DUSPs) that negatively regulate mitogen-activated protein kinase (MAPK) signaling pathways activated by Ang-1. Specifically we found that Ang-1 increased the expression (mRNA and Protein), as well as the activity of DUSP1, DUSP4 and DUSP5. Knocking down these phosphatases using siRNA revealed that DUSP1 mainly inactivates p38, DUSP4 dephosphorylates ERK1/2, p38 and SAPK/JNK, and DUSP5 is ERK-specific. Furthermore DUSP1, DUSP4 and DUSP5 had distinct functions in Ang-1-dependent survival and migration of endothelial cells (ECs).Because of the importance of angiogenesis in tumor progression, we then investigated the influence of estradiol (E2) on the expression of angiopoietins in breast cancer cell lines. We found Ang-1 mRNA and protein expressions to be lower in estrogen receptor (ERα) positive cells than in ERα negative cells. Additionally, we observed that both tumor size and Ang-1 production were reduced in ERα+ cell-derived xenografts in mouse mammary pads when compared to those derived from ERα- cells; and this effect was inhibited when the mice were ovariectomized. Since a large portion of the genome is under the regulation of microRNAs (miRNAs), we hypothesized that Ang-1 induces the expression of miRNAs to protect the endothelium against E. Coli lipopolysaccharide (LPS)-induced inflammation. We found that treating HUVECs for 24h with Ang-1 reduced LPS-induced phosphorylation of p38 and SAPK/JNK, and the activation of nuclear factor kappa b (NF-B). Ang-1 also decreased the expression of pro-inflammatory cytokines, adhesion molecules and leukocyte adhesion in vitro. Our findings suggest that miR-146b-5p is induced by Ang-1 as a mechanism to control Toll-like receptor (TLR) 4 signaling and the expression of pro-inflammatory mediators by targeting the signaling proteins interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6). We conclude that Ang-1 induces the expression of DUSP1, DUSP4 and DUSP5 to coordinate its anti-apoptotic and migratory response. Ang-1 is also an important modulator of growth and progression of ERα- breast cancers. Finally, Ang-1 treatment antagonizes pro-inflammatory pathways activated by LPS through the induction of miR-146b-5p which targets the TLR signaling proteins IRAK1 and TRAF6.L'angiogenèse et l'inflammation sont caractéristiques de plusieurs pathologies, dont le cancer du sein. Les angiopoiétines et les récepteurs Tie ont émergé comme cibles d'intervention thérapeutique alternatives en raison de leur fonction de régulateurs essentiels de l'angiogenèse, de l'homéostasie vasculaire et de l'inflammation. L'angiopoiétine-1 (Ang-1), l'agoniste principal du récepteur Tie-2, favorise la croissance des vaisseaux, inhibe l'inflammation et maintient la stabilité vasculaire. Bien que des progrès importants aient été réalisés dans la compréhension des fonctions d'Ang-1 dans le système vasculaire, les voies de signalisation intracellulaires activées par Ang-1 ainsi que son rôle dans le cancer du sein et l'inflammation sont largement inexplorées.Utilisant des cellules endothéliales de veine ombilicale (CEVOH), nous avons identifié des phosphatases à double spécificité (DSPs) qui régulent négativement les voies de signalisation des protéines kinase activée par mitogènes (MAPKs) activées par Ang-1. Plus précisément nous avons trouvé que l'Ang-1 a induit l'ARNm, l'expression des protéines et l'activité de DSP1, DSP4 et DSP5. Réduire l'expression de ces phosphatases à l'aide de ARNi a révélé que DSP1 inactive principalement p38, DSP4 déphosphoryle ERK1/2, p38 et SAPK/JNK et DSP5 est spécifique pour ERK. En outre DSP1, DSP4 et DSP5 possèdent des fonctions distinctes pour la régulation de la migration, la survie, la formation de tube capillaire et la perméabilité vasculaire dépendante d'Ang-1.En raison de l'importance de l'angiogenèse dans la progression tumorale, nous avons ensuite étudié l'influence de l'estradiol (E2) sur l'expression des angiopoiétines dans des lignées cellulaires du cancer du sein. Nous avons trouvé que le niveau de transcrits d'ARNm ainsi que l'expression protéique d'Ang-1 étaient réduits dans cellules positives pour les récepteurs des œstrogènes (ER) par comparison aux cellules négatives pour ER. En outre, nous avons observé que la taille de la tumeur et la production d'Ang-1 étaient réduits dans de xénogreffes de tissu mammaire chez la souris dérivés de cellules ER+, par rapport à ceux issus de cellules ER. De plus cet effet est inhibé lorsque les souris sont ovariectomisées.Comme une grande partie du génome est sous le contrôle des microARNs (miARN), nous avons émis l'hypothèse que l'Ang-1 induit l'expression des miARNs pour protéger l'endothélium contre l'inflammation induite par le lipopolysaccharide (LPS) d'E. Coli. Nous avons constaté que le traitement de CEVOH pendant 24 heures avec Ang-1 réduit la phosphorylation de p38 et SAPK/JNK, ainsi que l'activation du facteur nucléaire kappa B (NF-B) induite par le LPS. Ang-1 a également diminué l'expression de cytokines pro-inflammatoires, des molécules d'adhésion et l'adhérence des leucocytes in vitro. Nos résultats suggèrent que miR-146b-5p est induit par l'Ang-1 comme un mécanisme pour le contrôle de la signalisation des récepteurs de type toll (TLR) et l'expression de médiateurs pro-inflammatoires, en ciblant les protéines de signalisation IRAK1 et TRAF6.Nous concluons que l'Ang-1 induit l'expression de DSP1, DSP4 et DSP5 à fin de coordonner son action anti-apoptotique et sa réponse migratoire et angiogénique. Ang-1 est également un modulateur important de la croissance et de la progression des cancers du sein ER-. Enfin, le traitement avec Ang-1 antagonise les voies de signalisation pro-inflammatoires par l'induction de l'expression de miR-146-5p, qui cible des protéines de la voie de signalisation TLR: IRAK1 et TRAF6.
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Jonas, Wenke. "Untersuchung zur transkriptionellen Regulation des Angiopoietin-2 in humanen Endothelzellen." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2010. http://dx.doi.org/10.18452/16180.
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Angiopoietin-2 (Ang-2) wirkt gefäßdestabilisierend und ist Voraussetzung für das Aussprossen von Gefäßen am Anfang der angiogenen Kaskade. Die Expression des Antagonisten der endothelialen Rezeptor-Tyrosin-Kinase Tie-2 ist streng gewebsspezifisch reguliert. Trotz des Zusammenhangs von Ang-2 und pathologischer Angiogenese sind die molekularen Mechanismen der ang-2 Regulation noch unverstanden. Mittels Microarray wurden die genomweiten Expressionsänderungen in endothelialen Zellen nach Behandlung mit dem demethylierenden 5-Aza-2’-deoxycytidine (5-Aza-dC) untersucht. Unter den induzierten Genen wurde ang-2 mit dem Fokus auf angiogeneserelevante Gene identifiziert. Obwohl die Endothelzellen unter Kontrollbedingungen ang-2 exprimieren, wurde die Expression durch Demethylierung weiter gesteigert. Es wurden jedoch keine potentiellen CpG-Inseln in unmittelbarer Nähe des Transkriptionsstarts identifiziert. Diese Daten lassen auf einen methylierungsunabhängigen Effekt von 5-Aza-dC auf die ang-2 Expression schließen. Zur molekularen Untersuchung der ang-2 Expression wurden 3kb der 5´-flankierenden Sequenz des humanen ang-2 Gens kloniert und der Transkriptionsstartpunkt (TS) bestimmt. Durch funktionelle 5´-Deletionsanalyse und zielgerichtete Mutagenese wurden regulatorische Promotorelemente identifiziert. Die Promotorregion -105 bis +51 relativ zum TS war ausreichend für die Vermittlung der basalen ang-2 Expression. Mittels Bindungsstudien wurden die Transkriptionsfaktoren Sp1 und Sp3 als Proteine, die primär an den ang-2 Minimalpromotor binden, identifiziert. Die Basen -78 bis -74 relativ zum TS sind eine essentielle Sp-Bindestelle für die Regulation der ang-2 Expression. Durch Mutation von potentiellen Bindungsstellen für Proteine der ETS-Familie wurde die ang-2 Promotoraktivität signifikant reduziert. Jedoch konnte die Spezifität von ETS-Proteinen in Bindungsstudien nicht bestätigt werden. Die Ergebnisse dieser Arbeit haben neue Einblicke in die ang-2 Regulation offenbart und zeigen, dass die Sp1/Sp3-abhängige Aktivierung des proximalen Promotorbereichs (-105/-56) entscheidend für die transkriptionelle ang-2 Regulation in Endothelzellen ist.Angiopoitein-2 (Ang-2) acts destabilizing on blood vessels and is mandatory for the onset of the angiogenic cascade. The expression of the antagonistic ligand of the endothelial cell tyrosine kinase receptor Tie-2 is tightly regulated. Despite the accumulating evidence confirming the involvement of Ang-2 in pathologic angiogenesis, the molecular mechanisms controlling ang-2 expression are still unclear. Using microarray analysis, the global changes of gene expression were investigated after treatment of endothelial cells with the demethylating agent 5-aza-2’-deoxycytidine (5-aza-dC). Focusing on angiogenesis related genes, ang-2 was identified among the upregulated ones. Although endothelial cells expressed ang-2 under control conditions already the expression was further increased by drug-induced demethylation. A screen for CpG-islands revealed no putative islands surrounding the transcription initiation site. These data indicate a methylation-independent effect of 5-aza-dC on the ang-2 expression. To elucidate underlying molecular mechanisms of ang-2 expression, 3kb of the human ang-2 gene were cloned and the transcription start site (TS) determined. Regulatory promoter elements were identified by functional 5’-deletion analysis and site-directed mutagenesis. The promoter region -105 to +51 relative to TS was recognized as sufficient and necessary for the ang-2 gene transcription. Electrophoretic Mobility Shift Assays revealed Sp1 and Sp3 as dominant nuclear proteins binding to the ang-2 promoter. The region spanning -78/-74 was identified as essential Sp1/3 site regulating ang-2 expression. The mutation of potential ETS-binding sites resulted in a significant decrease of ang-2 promoter activity. However, the binding of ETS-proteins could not be confirmed by means of EMSA. The results of this thesis revealed new insights of ang-2 regulation and strongly suggest that Sp1/Sp3-dependent activation of an upstream enhancer at -105 to -56 is crucial for the regulation of ang-2 expression in endothelial cells.
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Sukonina, Valentina. "Angiopoietin-like protein 4 : an unfolding chaperone regulating lipoprotein lipase activity." Doctoral thesis, Umeå : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1343.
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Seegar, Tom CM. "TIED TOGETHER: A MOLECULAR ROLE FOR TIE1 IN ANGIOPOIETIN TIE2 SIGNALING." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/2122.
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The primary function of the vascular system is the maintenance of oxygen homeostasis for all metazoan tissue. Angiogenesis, the remodeling and maintenance of new blood vessels from an existing vessel, is primarily controlled through the endothelial specific receptor tyrosine kinase Tie2, and the orphan receptor tyrosine kinase, Tie1. Although these receptors share highly conserved, genetic and biochemical analysis has shown these receptors have distinct and essential roles in angiogenesis. Tie2 activation typically results in vessel stability and quiescences and has further been shown to interact with all four sub-types of the angiopoietin signaling factors, Ang1-4. Conversely, Tie1 is involved in vascular remodeling and has no known ligands. The aim of this study is to resolve the molecular mechanism in which Tie1 modulates Angiopoietin-induced Tie2 signaling. Using biophysical, structural, and biochemical assays we show Tie1 directly interacts with Tie2 via electrostatic interactions housed within the extracellular domains. The binding of Tie1 to Tie2 attenuates Tie2 phosphorylation. We further show the constitutive agonist of Tie2, Ang-1, is capable of excluding Tie1 initiating Tie2 activation. Whereas the antagonist, Ang-2, is in incapable of excluding Tie1. Finally, we identify a region within the angiopoietin receptor-binding domain that is capable of including or excluding Tie1 from Tie2. Based upon the available data, we provide a model for Angiopoietin-induced Tie2 signaling.
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Thomas, Markus. "Molecular mechanisms of Angiopoietin-2-mediated destabilisation of the vascular endothelium." [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:25-opus-62402.
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Vart, R. J. "Regulation of members of the angiopoietin family by Kaposi sarcoma herpesvirus." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1445893/.
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Kaposi sarcoma herpesvirus (KSHV) is the causative agent of Kaposi sarcoma (KS), a vascular tumour of endothelial cells. The angiopoictin family arc a group of secreted glycoproteins whose members play important roles in tumour vascularisation. The primary aim of this work was to investigate how KSHV regulated members of the angiopoictin family through the construction of a selected KSHV lentiviral expression library. Angiopoietin-2 (Ang2) is an important angiogenic factor which binds to the receptor Tie2 and is up-regulated in KS. Using a constructed KSHV lcntiviral library, viral interleukin-6 (vIL6) and viral G-protein-coupled receptor (vGPCR) were found to up-regulate Ang2 in lymphatic endothelial cells (LEC). Both vIL6 and vGPCR up-regulated Ang2 in a paracrine manner and caused an up-regulation of Ang2 through the mitogen-activated protein kinase pathway. Gene expression microarray analysis identified how other factors important for Ang2 function, and other members of the angiopoietin family, were regulated by KSHV infection of LEC. Angiopoietin-like 2 (Angptl2) has been shown to be important for proper vascularisation. My aim was to investigate the regulation of Angptl2 by KSHV and to start to investigate the function of Angptl2 in KS and cancer in general. Angptl2 is up-regulated in KS and in KSHV-infected LEC and is expressed in a variety of other neoplasms however, its expression profile did not correlate with expected angiogenic factors. The KSHV encoded viral interferon regulatory factor-1 (vIRFl) up-regulated Angptll expression in LEC and vIRFl increased Angpttt promoter activity using the first 1 kb of the Angptl2 promoter. Over-expression of Angptl2 in a mouse tumorigenesis model affected tumour growth resulting in smaller and more necrotic tumours. Ang2 and Angptl2 are likely to play important roles in KS pathogenesis. These angiopoietins along with the molecular mechanisms regulating their expression might present future targets for anti-KS therapeutics.
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Harfouche, Rania. "Modulation of endothelial cell survival by the angiopoietin-1Tie-2 receptor pathway." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=33771.
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The mechanisms by which Angiopoietin-1 (Ang-1) modulates the survival of human endothelial cells were investigated. Ang-1 inhibited both TNFalpha-induced and serum deprivation-evoked apoptosis, an effect which was associated with attenuation of caspase activation, inhibition of Smac release from the mitochondria, up-regulation of Survivin-1 expression (IAPs member) and a significant activation of the pro-survival PI-3 kinase/AKT pathway. In addition, Ang-1 activated, in a time-dependent fashion, both the anti-apoptotic ERK1/2 and pro-apoptotic p38 MAP kinases. Ang-1-evoked ERK1/2 activation was mediated in part through the PI-3 kinase pathway, whereas both, the PI-3 kinase and ERK1/2 attenuated p38 MAP kinase activation.We conclude that Ang-1 promotes endothelial cell survival through several pathways including the PI-3 kinase/AKT and ERK1/2 pathways, up-regulation of Survivin-1 as well as inhibition of Smac release and caspase activity. The preferential activation of these anti-apoptotic effects, as opposed to the activation of pro-apoptotic p38 MAP kinase, results in a net survival response.
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Sharma, Shikha. "Developing somatic hypermutation as a protein engineering tool to study angiopoietin binding." Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/10297.
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The angiopoietin (Ang) and Tie families play an important role in the latter stages of vascular development and in adult vasculature. A variety of studies on Ang1 ligand have provided compelling evidence of its therapeutic potential and along with Ang2 plays a major role in various protective and pathological conditions. Understanding the Ang-Tie interaction by manipulation of the angiopoietins is a very desirable prospect for developing it as a protein therapeutic drug. The aim of this project was to examine the molecular basis of Ang binding using a combination of rational mutagenesis and directed evolution. Directed evolution is a powerful strategy for protein engineering. A new method of directed evolution using mammalian surface display combined with mutagenesis driven by somatic hypermutation (SHM) was investigated for engineering Ang proteins with altered binding characteristics (to Tie1 and Tie2). The Ang receptor binding domains (RBD) were cloned linked to the asialoglycoprotein receptor (ASGPR) transmembrane domain. The fusion protein produced was capable of expression on the extracellular cell surface. Activation-induced (cytidine) deaminase (AID) expressing B cells were used for expression of this fusion protein. SHM driven by AID is capable of mutating highly expressed transgenes; this was used to generate the mutant library. The library was screened for enhanced Tie2 binding affinity and acquired Tie1 binding function by Fluorescence Activated Cell Sorting (FACS). Unstable expression of AID in the cell line and non-specific binding of Tie1 to the cell surface proteins in the binding screen prevented efficient selection of desired mutants. However, Ang2 FReD (fibrinogen-related domain) mutants were generated by SHM and rational mutagenesis. These were analysed and compared to the wild-type Ang2 FReD protein for expression by Western blotting and binding affinity determined by flow cytometry.
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Steele, Kathryn Helen. "Directed evolution of angiopoietin-binding proteins by somatic hypermutation and cell surface display." Thesis, University of Leicester, 2013. http://hdl.handle.net/2381/28037.
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Angiopoietin-2 (Ang2) is a secreted ligand that promotes blood vessel destabilisation, remodelling, leakage and inflammation in response to pro-inflammatory activators. In binding to its primary receptor, Tie2, it functions as a competitive antagonist of the anti-inflammatory and pro-quiescent agonist angiopoietin-1 (Ang1). Ang2 is markedly elevated in conditions associated with vascular dysfunction and therefore development of an Ang2 inhibitor has multiple potential clinical applications. Ligand traps are developed from native receptor ectodomain fragments and offer improved pharmacokinetics over monoclonal antibodies. However production of an Ang2-trap requires manipulation of the endogenous Tie2 receptor to permit Ang2 but not Ang1 binding, and this objective formed the inspiration for this study. The aim was to test whether the somatic hypermutation (SHM) gene diversification activity of B cells could be combined with cell surface display to create a streamlined system for evolving binding proteins. The data presented demonstrates that a cell surface-expressed Tie2 mutant library can be generated via single transfection of a chimeric Tie2 ectodomain-cell surface display construct into the hypermutating DT40 cell line. Subsequently selection of Ang2-binding phenotypes via fluorescently labelled-angiopoietin binding assay and Fluorescence Activated Cell Sorting (FACS) was repeated iteratively prior to sequencing ofTie2 from recovered cells. This approach was successful in isolating mutant forms of Tie2 with altered binding characteristics. Directed evolution is one of the most powerful approaches for manipulating binding properties of proteins but traditionally has involved laborious techniques including iterative cycles of mutagenesis, expression and selection with inter-species translation issues. This combination of vertebrate 'in-cell' diversification and 'on-cell' binding and selection demonstrates a sustainable approach for evolution of any protein.
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Peterson, Teresa Erin. "Dual Targeting of Angiopoietin-2 and VEGF Signaling for the Treatment of Glioblastoma." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:14226044.
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Glioblastoma (GBM) is the most common and aggressive brain tumor in humans. Because GBM is highly angiogenic, the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has now become the standard of care for treatment of recurrent GBM. However, GBMs rapidly become refractory to standard anti-VEGF therapy. It was previously demonstrated that vessel normalization and subsequent reduction of intracranial vasogenic edema accounts for a majority of the benefit from inhibiting VEGF-signaling in GBM. Also, ectopic over-expression of Ang-2 compromises the benefits of anti-VEGF receptor (VEGFR) treatment in mice and showed that circulating levels of Ang-2 rebound after an initial decrease in GBM patients treated with anti-VEGFR agents. This thesis examines the hypothesis that combined inhibition of VEGF and Ang-2 signaling can improve survival in murine models of GBM, and investigates potential underlying mechanisms.
The efficacy of cediranib, a pan-VEGFR tyrosine kinase inhibitor, combined with MEDI3617, an anti-Ang-2 neutralizing antibody, was tested in two orthotopic models of GBM (U87 and Gl261). Combination therapy improved survival in both models beyond that of the monotherapy arms and of control IgG by delaying Gl261 growth and increasing U87 necrosis. Combination therapy increased perivascular cell coverage in both tumor models and led to a more mature, normalized tumor vasculature than that in the tumors treated with cediranib alone. Importantly, combination therapy was as effective at controlling edema as cediranib. Vascular normalization with VEGF-blockade has been shown to convert an immunoinhibitory tumor microenvironment to an immunostimulatory one. Improved vessel normalization resulting from combined Ang-2 and VEGFR inhibition was associated with an increase in the number of M1-like (anti-tumor) tumor associated macrophages (TAMs) compared to the cediranib-treated tumors. Inhibition of TAM recruitment with an anti-colony stimulating factor-1 (CSF1) neutralizing antibody compromised the survival benefit of anti-Ang-2/VEGFR combination therapy.
The work described here provides new insight into a potential therapeutic strategy for the treatment of GBM and should inform of the design of clinical trials on this therapeutic combination.
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Schmidt, Thomas [Verfasser]. "Angiopoietin 1 und 2 als Biomarker bei Patienten mit pulmonaler Hypertonie / Thomas Schmidt." Gießen : Universitätsbibliothek, 2017. http://d-nb.info/1138565792/34.
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Gryczka, Corina. "Arteriovenöse Differenzierung humaner Endothelzellen: Einfluss von Wachstumsfaktoren, Hypoxie und Biomechanik." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2008. http://nbn-resolving.de/urn:nbn:de:bsz:14-ds-1225371163938-69534.
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Arterien und Venen sind aufgrund ihrer Funktion im Körper morphologisch, funktionell und genetisch unterschiedlich. Schon die großen Blutgefässe auskleidende Endothelzellen zeigen eine arteriovenöse Determinierung. Ausgehend von einer Mikroarray-Analyse der mRNA-Expression arterieller und venöser Endothelzellen der Nabelschnur wurde im Rahmen dieser Arbeit auf Moleküle des Notch-Signalwegs, Dll-4, Notch-4, Hey-1 und Hey-2 fokussiert, die präferenziell bis exklusiv arteriell exprimiert werden. Weitere Gene mit einem arteriellen Expressionsmuster, die im Rahmen der vorliegenden Arbeit analysiert wurden, sind Angiopoietin-2 und CD44s. Trotz der genetisch definierten Unterschiede ließ der Vergleich physiologisch relevanter Funktionen, wie Proliferation oder die Interaktion mit monozytären Zellen keinen vom endothelialen Zelltyp abhängigen Unterschied erkennen. Die im Matrigel ausgebildeten kapillar-ähnlichen Strukturen sind durch homogene, eng beieinander liegende Netzwerke charakterisiert. Studien über den Einfluss von Wachstumsfaktoren und Schubspannung auf die arteriovenöse Expression von Angiopoietin-2 deuten auf eine schubspannungsvermittelte Regulation der Gefäßstabilität und Differenzierung hin. Die in der Zellkultur durchgeführten Manipulationen, wie der Einfluss verschiedener Wachstumsfaktoren oder die Applikation unterschiedlicher Schubspannungen, erreichten in Bezug auf die Expression der untersuchten Markergene keine tiefer greifende Redifferenzierung des jeweiligen endothelialen Phänotyps. Der evolutionär hoch konservierte Notch-Signalweg ist präferenziell arteriell exprimiert, wobei Hey-2 ausschließlich arteriell exprimiert wird. In adulten Endothelzellen erfolgt die Hey-2-Regulation jedoch Notch-unabhängig. Die arteriovenöse Genexpression von Molekülen des Notch-Signalwegs ist unabhängig von der Schubspannung. Unter hypoxischen Bedingungen verringerte sich die Expression von Dll-4, Hey-1 / 2 dramatisch, ohne das jedoch physiologische Beeinträchtigungen zu beobachten waren. Die Expression des venösen COUP-TF II wird in arteriellen Endothelzellen nicht durch den Notch-Signalweg reguliert. Die Auswertung der Daten in der vorgelegten Arbeit lässt vermuten, dass die einmal festgelegte genetische Determinierung adulter Endothelzellen fixiert und äußeren Einflüssen gegenüber stabil und unumkehrbar ist. Dennoch ist eine gewisse Anpassungsfähigkeit der Endothelzellen an bestimmte Situationen möglich, die zwar die Ausprägung von Merkmalen des jeweilig anderen Phänotyps beinhaltet, jedoch nicht eine vollständige Redifferenzierung.
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Wagner, Patrick. "Analyse der Wirkung von Angiopoietin-2 auf das Gefässsystem der Netzhaut in verschiedenen Tiermodellen." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=976086360.
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Milner, Chris Stephen. "Studies into angiopoietin-1 and Tie receptor signalling during endothelial responses to acute inflammation." Thesis, University of Leicester, 2008. http://hdl.handle.net/2381/29907.
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Endothelial dysfunction is a major component of the systemic inflammatory response syndrome (SIRS) triggered by major injury including burns. Angiopoietin-1, a key regulator of angiogenesis operates through two different receptors, Tie1 and Tie2. Identifying specific roles of each receptor in mediating the protective effects of Ang1 is essential for designing drug therapy for pathological inflammatory responses. In vitro models of endothelial permeability, survival and adhesion molecule expression have been established to study the effects of Ang-1 on Tie receptor deficient HUVEC generated by SiRNA techniques. Tie receptor knock-down was highly effective in HUVEC, and subsequent experiments using these cells proved the hypothesis that Tie2 is the principal receptor mediating Ang-1 induced endothelial survival and reduced endothelial permeability. In addition, absent Tie1 was found to increase baseline endothelial permeability and apoptosis in HUVEC, whilst the full anti-apoptotic effect of VEGF was shown to require both Tiel and Tie2, adding to other data indicating a novel form of heterodimeric transactivation between the two receptors. Using the developed cell adhesion molecule (CAM) assay, experiments using naive HUVEC quantitated the anti-inflammatory effects of Ang-1 following stimulation by key pro-inflammatory cytokines such as Il-1. Moreover, preliminary experiments using plasma from patients with SIRS demonstrated the usefulness of the inflammatory CAM assay as a model for studying endothelial inflammatory responses in humans. Finally, experiments combining SIRS plasma with Ang-1 demonstrated a possible role for Ang-1 in the inhibition of SIRS plasma induced CAM expression.
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Bezuidenhout, Louise. "Angiopoietin-2 and platelet-derived growth-BB factor cooperatively affect peripheral blood monocyte fibrinolysis." Doctoral thesis, University of Cape Town, 2007. http://hdl.handle.net/11427/3362.
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Ebert, Thomas. "Untersuchungen zu Angiopoietin-related Growth Factor bei Präeklampsie, chronischer Dialysepflicht und Diabetes mellitus Typ 2." Doctoral thesis, Universitätsbibliothek Leipzig, 2010. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-63709.
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Adipositas ist besonders in den Industrienationen ein zunehmendes gesellschaftliches und ökonomisches Problem. Dabei sind vor allem die kardiovaskulären und metabolischen Begleiterkrankungen von entscheidender Bedeutung. In den letzten Jahren konnte gezeigt werden, dass verschiedene Adipozyten- und Hepatozyten-sezernierte Proteine Mediatoren von Insulinresistenz und Dyslipidämie darstellen. Kürzlich wurde Angiopoietin-related growth factor (AGF) als ein neues, von der Leber produziertes Protein, das potentiell Insulinresistenz und Adipositas antagonisiert, vorgestellt. Im Mausmodell waren AGF-überexprimierende Tiere schlanker und insulinsensitiver verglichen zu Kontrolltieren. Zudem entwickelten AGF-knockout-Mäuse eine Adipositas, Insulinresistenz sowie eine Leber- und Skelettmuskelverfettung. Weiterhin fand sich in epidermalen Keratinozyten eine Hypervaskularisierung bei transgenen Mäusen mit AGF-Expression. Dies macht AGF möglicherweise zu einem Zielgen in der Behandlung moderner Zivilisationskrankheiten, wie z.B. dem Diabetes mellitus Typ 2 (DMT2). Bisherige Publikationen über AGF basieren zumeist auf Tiermodellen. Über die Regulation beim Menschen existieren dagegen bislang nur wenige Studien.
In der vorliegenden Arbeit wurde AGF im Serum verschiedener Patientenpopulationen mit einem erhöhten kardiovaskulären Risikoprofil (Patienten mit chronischer Dialysepflicht, DMT2, Präeklampsie [PE]) mittels enzyme-linked immunosorbent assay quantifiziert und mit Kontrollpatienten verglichen. Die Ergebnisse zeigen, dass AGF bei Patienten mit DMT2 im Vergleich zu Nichtdiabetikern signifikant erhöht ist. Bei terminal-niereninsuffizienten Patienten dagegen fanden sich signifikant niedrigere AGF-Konzentrationen im Serum. Bei PE-Patientinnen waren signifikant höhere AGF-Spiegel nachweisbar verglichen zu gesunden schwangeren Kontrollen. Die vorgestellten Daten weisen darauf hin, dass erhöhte AGF-Spiegel bei DMT2 und PE eine physiologische Gegenregulation darstellen könnten, die der Insulinresistenz bei DMT2 bzw. antiangiogenetischen Faktoren bei PE entgegenwirkt. Alternativ wäre – ähnlich der Insulinresistenz – eine Resistenz von Patienten mit DMT2 bzw. PE gegen AGF möglich mit einer reflektorischen Erhöhung dieses Hepatozyten-exprimierten Faktors.
Die genaue Rolle von AGF bei kardiovaskulären Risikopatienten muss in zukünftigen Arbeiten noch weiter aufgeklärt werden.
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Deters, Antje [Verfasser]. "Expression und biologische Relevanz von Angiopoietin-2 in neuroendokrinen Tumoren des gastroenteropankreatischen Systems / Antje Deters." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2012. http://d-nb.info/1026882982/34.
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Ziegler, Tilman [Verfasser], and Christian [Akademischer Betreuer] Kupatt. "Mikrozirkulatorische und hämodynamische Veränderungen durch pan-endotheliale Angiopoietin-2 Überexpression / Tilman Ziegler. Betreuer: Christian Kupatt." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1063278724/34.
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王, 英泰. "Hypoxia and vascular endothelial growth factor selectively upregulate angiopoietin-2 in bovine microvascular endothelial cells." Kyoto University, 2001. http://hdl.handle.net/2433/150200.
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Rehm, Vanessa Annina [Verfasser]. "Angiopoietin-2 als Serummarker zur Diagnostik des hepatozellulären Karzinoms und der Leberzirrhose / Vanessa Annina Rehm." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2009. http://d-nb.info/1027497691/34.
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Liabotis-Fontugne, Athanasia. "Régulation dépendante du contexte de la morphogenèse et de l’intégrité capillaire par angiopoietin-like 4." Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS072.
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L’angiogenèse, indispensable à la mise en place d’un réseau vasculaire fonctionnel, est au cœur des stratégies thérapeutiques des pathologies ischémiques. L’hypoxie, caractérisant ces tissus ischémiques, est un stimulus majeur de l’angiogenèse, en induisant l’expression de facteurs de croissance tels que le VEGF et de protéines de la matrice extracellulaire endothéliale. Nous avons identifié la protéine ANGPTL4, comme une cible majeure de l’hypoxie et ayant des effets opposés au VEGF sur la perméabilité vasculaire. Le but de cette thèse a consisté en l’analyse du rôle d’ANGPTL4 sur la formation de capillaire et l’organisation des jonctions adhérentes dans un contexte dépendant du VEGF. J’ai démontré que le VEGF stimule la formation d’un dense réseau capillaire 3D alors qu’ANGPTL4 induit la formation de capillaires étroits et peu ramifiés. ANGPTL4 réduit la taille du réseau de capillaire induit par le VEGF en limitant le nombre de bourgeons, de branchements et la largeur des capillaires. ANGPTL4 renforce l’intégrité des capillaires formés en présence de VEGF en préservant des jonctions adhérentes stables. J’ai démontré qu’ANGPTL4 limite les processus de migration 3D et de prolifération induits par le VEGF. L’analyse de la voie de signalisation VEGF/ANGPTL4 a montré une potentialisation par ANGPTL4 de la phosphorylation Y1175 du VEGFR2, impliqué dans l’internalisation de VEGFR2. En conclusion, ce modèle révèle un effet d’ANGPTL4 dépendant du contexte 3D, qui stimule les processus d’angiogenèse en absence de VEGF et qui contrecarre la morphogenèse induite par le VEGF en renforçant l’intégrité des jonctions adhérentes et en régulant la signalisation en aval du VEGFR2Angiogenesis, by promoting new functional capillaries, is a main target of therapeutic strategies of ischemic pathologies. Ischemic tissues are characterized by hypoxic environment, which stimulates angiogenesis by inducing expression and secretion of growth factors such as VEGF and by remodeling endothelial extracellular matrix. Our team identified ANGPTL4 as a hypoxia-induced target and characterized its counteracting effect on VEGF-induced vascular permeability. This PhD study therefore aimed to decipher the role of ANGPTL4 on angiogenesis, capillary architecture and adherens junction (VE-cadherin) organization in a VEGF-dependent context. I demonstrated that VEGF induced formation of branched capillaries forming a dense 3D network while ANGPTL4 enhanced the formation of unbranched and tight capillaries. Remarkably, ANGPTL4 reduces VEGF-induced angiogenesis, by limiting branching and widening of the capillaries. Furthermore, ANGPTL4 regulates the local VE-cadherin patterning during the sprouting process by maintaining lateral linear structures and limiting the VEGF-induced formations involved in the migratory capacities. I demonstrated that ANGPTL4 limited VEGF-induced 3D endothelial cell migration and proliferation. Analysis of VEGF/ANGPTL4 signaling pathway pointed out that ANGPTL4 enhanced phosphorylation of Y1175 VEGFR2, known to enhance internalization of VEGFR2. In conclusion, this study modeled the 3D context-dependent effect of ANGPTL4 that stimulates angiogenesis in absence of VEGF whereas it counteracts VEGF-induced endothelial morphogenesis by regulating VEGFR2 trafficking and strengthening adherens junctions
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Bolin, Marie. "Pre-eclampsia – Possible to Predict? : A Biochemical and Epidemiological Study of Pre-eclampsia." Doctoral thesis, Uppsala universitet, Institutionen för kvinnors och barns hälsa, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-183394.
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Pre-eclampsia is a major cause of maternal and perinatal morbidity and mortality worldwide. A predictor of pre-eclampsia would enable intervention, close surveillance and timely delivery, and thereby reduce the negative consequences of the disorder. The overall aim of this thesis was to study potential predictors of pre-eclampsia by biochemical and epidemiological methods. Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) are regulators of angiogenesis, which is important for placental development. In a prospective and longitudinal study of a low-risk population the Ang-1/Ang-2 ratio was evaluated. The Ang-1/Ang-2 ratio increased during pregnancy in all women but at gestational week 25 and 28 the ratios were significantly lower in women who later developed pre-eclampsia. The relevance of Histidine-rich glycoprotein (HRG), a protein with angiogenic properties, was furthermore evaluated. HRG levels decreased in all women, with significantly lower levels at gestational week 10, 25 and 28 in women who later developed pre-eclampsia. Thus both Ang-1/Ang-2 ratio and HRG may predict pre-eclampsia. To evaluate the predictive value of HRG in combination with uterine artery Doppler early in pregnancy a study was performed in a high-risk population. The results revealed that the combination was better able to predict preterm pre-eclampsia than each marker individually, with a sensitivity of 91% at a specificity of 62%. A possible association between hyperemesis gravidarum and pre-eclampsia, as well as other placental dysfunctional disorders, was investigated. Hyperemesis gravidarum may be caused by high levels of human chorionic gonadotrophin (hCG) and increased levels of hCG in the second trimester is associated with later development of pre-eclampsia. A cohort of all pregnancies in the Swedish medical birth register between 1997 and 2009 was studied. After adjustment for confounding factors an association between hyperemesis gravidarum in the second trimester and preterm pre-eclampsia, placental abruption and infants born small for gestational age was demonstrated. In conclusion, the ratio of Ang-1/Ang-2 as well as HRG in plasma may be potential predictors of pre-eclampsia. Combination with uterine artery Doppler further increases the predictive value of HRG for preterm pre-eclampsia. Hyperemesis gravidarum in the second trimester may be considered as a clinical risk predictor of pre-eclampsia and other placental dysfunctional disorders.
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Lask, Aina [Verfasser]. "Therapeutische Bedeutung eines Angiopoietin-1 Mimetikums für den beatmungsassoziierten Lungenschaden in der murinen Pneumokokkenpneumonie / Aina Lask." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2021. http://d-nb.info/1241538743/34.
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Dellinger, Mike. "Contrasting Defects in Lymphangiogenic Remodeling and Lymphangiogenesis Revealed in Angiopoietin-2 Deficient and Vegfc Hemizygous Mice." Diss., The University of Arizona, 2008. http://hdl.handle.net/10150/195639.
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Despite recent advances in lymphology, the molecular mechanisms regulating the development of the lymphatic system have not been fully delineated. Here I show that the growth factors Angiopoietin-2 (Ang2) and Vascular endothelial growth factor-c (Vegfc) serve distinct roles in the development of the lymphatic system.Adult Ang2-/- mice exhibit dermal lymphatic hypoplasia, abnormal smooth muscle cell (SMC) coverage of initial lymphatic vessels, and a severe deficiency of collecting lymphatic vessels. To determine whether these abnormalities were due to defects in the remodeling of the lymphatic vasculature, I characterized this process in Ang2-/- mice. Indeed, lymphatic vessels in the skin of Ang2-/- pups prematurely recruited SMCs and did not mature into collecting vessels during the remodeling stage of lymphatic development. In contrast, Ang2 knockout Ang1 knock-in mice did develop a hierarchal lymphatic vasculature, suggesting that activation of Tie-2 is required for normal lymphatic development. To further delineate the molecular mechanisms regulating lymphatic development, I also characterized Chylous ascites-3 (Chy-3) mice, a strain missing cytobands 8A4 to 8B3 from one copy of chromosome 8. Real-time PCR using genomic DNA demonstrated that the lymphangiogenesis gene, Vegfc, was included in the deleted region. All of the key components of a normal lymphatic network had developed in Chy-3 mice; however, the number of lymphatic vessels was reduced. Although the patterning of lymphatic vasculature in Chy-3 mice was altered, the architecture of the blood vasculature appeared normal. Ang2-/- and Chy-3 mice are grossly indistinguishable from one another; however, their underlying lymphatic defects are dramatically different. Ang2-/- mice exhibit defects in lymphangiogenic remodeling and lymphangiogenesis, whereas Chy-3 mice show a reduced capacity for lymphangiogenesis. I propose that Ang2 maintains lymphatic vessel plasticity by preventing SMC-lymphatic vessel associations so maturation can occur and facilitates lymphangiogenesis in the presence of Vegfc. This is analogous to Ang2's function on the blood vasculature where it is thought to destabilize SMC-blood vessel interactions and facilitate hemangiogenesis in the presence of Vegfa.Taken together, these findings further delineate the development of the lymphatic system and could provide translational clues relevant to the pathogenesis and treatment of clinical disorders of the lymphatic system.
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Gilles, Maud-Emmanuelle. "Rôle d'un antagoniste de la nucléoline de surface : le N6L, sur la régulation de l’angiogenèse tumorale dans le modèle de l'adénocarcinome ductale pancréatique." Thesis, Paris Est, 2015. http://www.theses.fr/2015PESC0034.
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Dalton, Annamarie. "Regulation of Tie2 Extracellular Complex Formation in Angiogenesis." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3780.
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Pathological angiogenesis is an essential component of tumor growth, development, and metastasis for which few effective therapeutic options exist. Though many cancer therapies target the function of cell surface receptors, mechanisms regulating membrane receptor crosstalk remain unclear. Two important families of receptors in angiogenesis, the Ties and Integrins, respond to the extracellular environment via outside-in and, in the case of Integrins, also inside- out signaling. Recent reports showed that the endothelial specific tyrosine kinase receptor, Tie2, forms complexes with two of the endothelial Integrin heterodimers, α5β1 and αVβ3, providing a convenient mechanism for the integration of extracellular stimuli. Our data confirm the interaction between Integrins and Tie2 and additionally indicate an interaction with the orphan co-receptor Tie1. To elucidate the biological role of these macromolecular complexes, biochemical and biophysical methods including co-immunoprecipitation, FRET microscopy, and cellular based assays were used to follow receptor/Integrin association in response to the Tie2 ligands Angiopoietin-1 and -2 as well as the Integrin ligand fibronectin. Furthermore, structural analysis by small angle x-ray scattering of Tie2-ligand complexes and specific Integrin and Tie complexes are being used to identify the basis for growth factor receptor and Integrin signal transduction.
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Huse, Isabelle. "Untersuchungen zur Rolle der angiogenetischen Wachstumsfaktoren VEGF und Angiopoietin im zyklischen Endometrium und bei der embryonalen Implantation." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=966442008.
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Tamagno, Sara. "Characterization of the role of angiopoietin-tie signalling in haematopoietic stem cell development in the murine embryo." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31056.
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Haematopoietic stem cells (HSCs) are capable of self-renewing and multi-lineage reconstitution of the haematopoietic system of irradiated recipient mice. In the mouse embryo, HSCs originate in a step-wise manner from the haematogenic endothelium. The first HSC precursor has been detected at E9.5 in the dorsal aorta, while HSCs emerge in the aorta-gonad-mesonephros (AGM) region around E11. To date, the molecular mechanisms regulating these events are poorly characterized. Through the activating role of Angiopoietin1 (Ang1) on Tie2 receptor, the Ang-Tie signalling pathway plays a critical role in HSC maintenance in the adult bone marrow niche. Tie2 ligand Angiopoietin2 (Ang2) is described as being a Tie2 inhibitor, however its role is unknown. The aim of this thesis was to characterise the role of Ang-Tie signalling pathway in HSC formation in the mouse embryo. First, I used an ex vivo aggregate system to culture with angiopoietins cells derived from the AGM region at stages of development preceding HSC formation (E9.5-E11). Ang2- treated cells were able to reconstitute the peripheral blood of recipient mice to a higher extent compared to control, indicating a role for Ang2 in promoting HSC maturation. Then, I characterized the expression pattern of Ang-Tie molecules in the AGM region. Ang2-expressing cells were identified as perivascular and sub-aortic mesenchymal cells located in the ventral side of the aorta and in proximity of intra-aortic haematopoietic clusters. Finally, I performed an RNA-seq analysis with the aim of unravelling the molecular mechanisms involved in Ang2-mediated HSC maturation. Pre-HSC-I were cultured in presence or absence of Ang2 and their transcriptional profiles were compared, revealing a number of genes and pathways up-regulated or down-regulated in presence of Ang2, which might indicate a role for Ang2 in increasing cell proliferation, favouring cell migration, and regulation of other signalling pathways involved in HSC development. All together, these data support Ang2 as a novel regulator for HSC formation.
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Neuneier, Janina Lara [Verfasser]. "Serum Angiopoietin-2 als prognostischer und prädiktiver Faktor in der Therapie des kolorektalen Karzinoms / Janina Lara Neuneier." Köln : Deutsche Zentralbibliothek für Medizin, 2011. http://d-nb.info/1012219194/34.
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Müller, Kristin. "Morphologisch-funktionelle Untersuchungen zur Angiogenese in equinen Granulosazelltumoren im Vergleich zum unveränderten Stutenovar." Doctoral thesis, Universitätsbibliothek Leipzig, 2008. http://nbn-resolving.de/urn:nbn:de:bsz:15-20080421-072252-1.
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Das Ziel der Arbeit war eine Charakterisierung der Angiogenese im unveränderten Stutenovar sowie in equinen Granulosazelltumoren (GZTt). In diesem Zusammenhang sollte das Vorkommen und die Bedeutung ausgewählter angiogener Faktoren und ihrer Rezeptoren in den genannten Geweben ermittelt werden. Darüber hinaus war zu klären, inwieweit histomorphologische und immunhistologische Untersuchungen bezüglich der Angiogenese einen Beitrag zur Charakterisierung der biologischen Wertigkeit equiner Granulosazelltumoren liefern können. Für die Untersuchungen standen 71 Granulosazelltumoren 70 einseitig ovariektomierter Tiere und einer euthanasierten Stute, bei der eine ausgedehnte abdominale Metastasierung des Tumors festgestellt wurde, zur Verfügung. Als Kontrolle dienten die unveränderten Ovarien von 20 Stuten (Sektion n=8, Ovariektomie n=2, Schlachthof n=10). Darüber hinaus wurden bei 46 Stuten mit GZTt die Serumhormonwerte (Östradiol, Progesteron und Testosteron) bestimmt. Die unveränderten Ovarien sowie die GZTt wurden zunächst pathologisch-anatomisch untersucht, in Formalin (4%) fixiert und routinemäßig für die Histologie aufgearbeitet. Mittels konventioneller Lichtmikroskopie (Hämalaun-Eosin-Färbung) erfolgte anschließend eine repräsentative Auswahl von verschiedenen Funktionskörpern (n=66) des unveränderten Ovars sowie von GZTt unterschiedlicher Wachstumsformen (n=21 sowie eine Metastase des malignen GZT), an welchen die immunhistolo-gischen Untersuchungen (vascular endothelial growth factor A (VEGF A), vascular endothelial growth factor B (VEGF B), vascular endothelial growth factor receptor 1 (VEGF-R1), vascular endothelial growth factor receptor 2 (VEGF-R2), Angiopoietin 1 (Ang1), Angiopoietin 2 (Ang2), Angiopoietinre-zeptor (Tie2), von Willebrand Factor) durchgeführt wurden. Es kann festgestellt werden, dass im unveränderten zyklischen Stutenovar die intensivste Koexpression der angiogenen Faktoren VEGF A, VEGF B, Ang1, Ang2 und ihrer Rezeptoren VEGF-R1, VEGF-R2 und Tie2 in den Granulosa- und Thekazellen sowie den vaskulären Strukturen der Thekazellschicht im periovulatorischen (Tertiär-/Graaf´sche Follikel bis Corpora haemorrhagica) Zeitraum, der Phase der am deutlichsten ausgeprägten Angiogenese im Ovar, nachgewiesen werden kann. Zum einen ist dies für die Erhaltung und Reifung eines Follikels bis zum sprungreifen Tertiärfollikel essentiell, zum anderen findet kurz nach der Ovulation eine so ausgeprägte Angiogenese statt, dass schließlich alle Luteinzellen des reifen C. luteum mindestens einen Kontakt zu den neugebildeten Gefäßen besitzen. Somit wird eine optimale Erfüllung der Funktion des C. luteum als temporär endokrine Drüse für die Progesteronsynthese gewährleistet. Im eigenen Untersuchungsgut können hinsichtlich des Expressionsmusters gewisse Ähnlichkeiten zwischen dem unveränderten zyklischen Ovar und den benignen GZTt festgestellt werden. Insbesondere die neoplastischen Granulosazellen und Leydig-like cells erinnern in ihrem Expressionsverhalten bezüglich der untersuchten angiogenen Faktoren/Rezeptoren an die Granulosazellen beziehungsweise die luteinisierten Thekazellen des periovulatorischen zyklischen unveränderten Ovars. Zum einen lassen diese Befunde den Schluss zu, dass die neoplastischen Granulosazellen und Leydig-like cells der untersuchten Tumoren, entsprechend den periovulatorischen Granulosazellen und Thekazellen des zyklischen Ovars, infolge der Expression der angiogenen Faktoren und ihrer Rezeptoren einen wesentlichen Beitrag zur Angiogenese und damit zur Durchblutung, zur Versorgung und zum Wachstum der GZTt leisten. Andererseits kann durch die Ähnlichkeit im Expressionsmuster der genannten Zellen auch mittels der durchgeführten Untersuchungen gezeigt werden, dass es sich bei den equinen Granulosazelltumoren um weitgehend gut differenzierte Neoplasien handelt. Trotzdem ist in Einzelfällen mit einer Metastasierung zu rechnen. Die konventionelle Histopathologie liefert diesbezüglich jedoch keine verwertbaren Anhaltspunkte. Mittels der immunhistologischen Untersuchungen kann aufgezeigt werden, dass zwischen benignen und malignen Granulosazelltumoren partiell ein verändertes Expressionsverhalten bezüglich der untersuchten angiogenen Faktoren und ihrer Rezeptoren existiert. Inwieweit diese Abweichung jedoch als hinweisend für eine potenzielle Malignität interpretiert werden kann, ist aufgrund der zu geringen Probenanzahl maligner Neoplasien abschließend nicht beurteilbar und Bedarf einer Konkretisierung der bisherigen Ergebnisse an einem größeren Untersuchungsgut.