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1
Li, Xiaobo. "PHYSICAL INTERACTIONS BETWEEN NEUROPILIN AND VEGFRS, INTEGRINS IN REGULATING ENDOTHELIAL CELL FUNCTIONS". UKnowledge, 2015. http://uknowledge.uky.edu/biochem_etds/23.
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The neuropilin (Nrp) family consists of multifunctional cell surface receptors with critical roles in a number of different cell and tissue types. A core aspect of Nrp function is ligand-dependent cellular adhesion and migration, where it controls the multistep process of cellular motility through integration of ligand binding, receptor coupling and signaling via the coordinated action of its extracellular and intracellular domains. While Nrp regulates cellular adhesion and motility in the cardiovascular and nervous systems under physiological conditions, the emerging pathological role of Nrp in tumor cell migration and metastasis has been identified and provides motivation for continued efforts toward developing Nrp inhibitors.
At the molecular level, the role of Nrp in adhesion and migration is intimately connected to the control of adhesive interactions and cytoskeletal reorganization. The adhesive “interactome” for Nrp draws much attention because of its lack of enzymatic activity and inability to transduce signals on its own. It is an active area of research and is still expanding dramatically. Nrp has been well defined as a co-receptor for vascular endothelial growth factor receptor (VEGFR)/vascular endothelial growth factor (VEGF) signaling through enhancing receptor-ligand interaction in angiogenesis. Here, we contribute to this concept through characterization in more biochemical detail about Nrp-1/VEGF physical interactions. VEGF has been shown to compete with Sema3 for binding to Nrp-1 b1 ligand binding pocket. This competition fine-tunes VEGF-induced angiogenesis. Our data provides a molecular mechanism for high affinity Sema3F binding to Nrp-1 in the b1 domain. As to the VEGFR-independent function, Nrp/integrin association has been demonstrated. The functional integration has been shown for Nrp/integrin in angiogenic sprouting. Both proteins are highly expressed in endothelial tip cells to mediate endothelial cell migration during angiogenesis and knockdown of either one in mice leads to embryonic lethality due to similar defects in vascular development. To identify the structure and function correlation, we characterized in more detail about Nrp-1/integrin physical interactions with biochemical and cell-based assays. Through an integrated approach of biochemical, molecular and cellular methods, we defined the direct physical interactions between Nrp-1 and integrins. We have also extended this work to demonstrate the functional importance and contribution of the interactions in integrin-mediated cell adhesion on extracellular matrix (ECM) in angiogenesis and platelet function during wound healing and provide a molecular basis for the integration of Nrps/integrins in cell migration, adhesion to ECM, breast cancer initiation and breast cancer stem cell fate determination.
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Abe, Daniel Kanda. "Análise da expressão dos genes CD105 (endoglina), VEGF, VEGFR1 e VEGFR2 no carcinoma de células renais e correlação com fatores prognósticos". Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5153/tde-02102013-094530/.
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INTRODUÇÃO: A angiogênese tem sido proposta como um marcador de prognóstico em uma variedade de tumores incluindo o renal. No avanço da compreensão da biologia molecular do carcinoma de células renais (CCR) os genes CD105 (endoglina), VEGF, VEGFR1 e VEGFR2 são seletivamente expressos em células endoteliais vasculares sendo estudados como potenciais alvos terapêuticos. OBJETIVOS: Este estudo analisou a expressão destes quatro genes no tecido renal normal e CCR e suas correlações com os fatores prognósticos para a neoplasia. MÉTODOS: Os níveis de expressão de CD105, VEGF, VEGFR1 e VEGFR2 foram analisados por Reação da Transcriptase Reversa em tempo real (qRT-PCR) em amostras de tumor fresco congelado coletados de 56 pacientes submetidos à nefrectomia parcial ou radical por CCR. Neste estudo foram avaliados os níveis de expressão dos genes em tecidos normais e tumorais e comparados com fatores prognósticos como tamanho tumoral (> ou <= 7 cm), Grau de Fuhrman (1-2 e 3-4) e invasão microvascular (presente ou ausente). RESULTADOS: A análise dos quatro genes demonstrou que CD105 esta subexpresso em 94.7% dos casos e a superexpressão de VEGF, VEGFR1 e VEGFR2 ocorreu em 53,6%, 85,7% e 64,3% dos casos respectivamente. A expressão de endoglina foi significativamente maior em pacientes com doença metastática (p=0,05) em relação ao grupo sem metástases. Além disso, o gene do VEGFR2 foi associado com estadiamento T, apresentando uma média de expressão maior nos pacientes portadores de doença pT1-2 (p=0,04). CONCLUSÕES: Nossos experimentos demonstraram que a endoglina está subexpressa em carcinoma de células renais em relação com o tecido renal normal e a presença de níveis mais elevados está relacionada à doença metastática. Os genes VEGF, VEGFR1 e VEGFR2 encontram-se superexpressos no CCR e uma maior expressão do gene VEGFR2 está relacionada com estadiamento T1 e T2INTRODUCTION: Angiogenesis has been proposed as a prognostic marker in a variety of human malignancies, including renal cancer. Due to a better understanding of the underlying biology of Renal Cell Carcinoma (RCC) the genes expression of CD105 (endoglina), VEGF, VEGFR1 and VEGFR2 that are selectively expressed in vascular endothelial cells are being studied as potential therapeutic targets. OBJECTIVES: This study analyzed the expression of these four genes in normal kidney tissue and RCC and relationship with prognostic factors. METHODS: CD105, VEGF, VEGFR1 and VEGFR2 expression levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) in fresh-frozen malignant tissue specimens collected from 56 patients submitted to radical or partial nephrectomy. This study assessed the expression of genes in normal and tumor tissues, and compared with classic prognostic parameters in CCRCC , such as tumor size (larger or smaller than 7 cm) Fuhrman grade (1-2 and 3-4) and microvascular invasion (this or absent). RESULTS: The analysis of these four genes showed that CD105 is subexpressed in 94.7% of cases and the overexpression of VEGF, VEGFR1 and VEGFR2 occurred in 53.6%, 85.7% and 64.3% of cases respectively in tumor tissues compared to controls. The expression of endoglin was significantly higher in patients with metastatic disease (p = 0.05). In addition, VEGFR2 gene was associated with stage T, with an average of expression higher in patients with stage T1-T2 (p = 0.040). Conclusions: These experiments demonstrated that endoglin was underexpressed in RCC compared to normal kidney and the presence of enhanced expression is associated with metastatic disease. VEGF, VEGFR1 and VEGFR2 were overexpressed in the CCRCC and a higher VEGFR2 expression was related with stage T1-2
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ORTEGA, NATHALIE. "Role de la biodisponibilite du vegf et des fonctions induites par chacun des recepteurs, vegfr1 et vegfr2, dans l'initiation du processus angiogenique". Toulouse 3, 1999. http://www.theses.fr/1999TOU30064.
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L'angiogenese est un processus invasif, aboutissant a la formation de nouveaux vaisseaux a partir de vaisseaux preexistants. Le facteur primordial de ce processus est le vegf (vascular endothelial growth factor). Il existe sous six isoformes qui different par leur solubilite et leurs activites biologiques. L'isoforme de 189 acides amines (v189) differe de l'isoforme 165 (v165) par la presence d'une sequence tres basique codee par l'exon 6. Deux recepteurs tyrosine kinase sont connus pour ces facteurs : vegfr1 et vegfr2. En comparant les activites biologiques de v165 et v189 nous avons montre la dualite du mode d'action de v189. Cette isoforme agit non seulement par les voies de vegfr1 et vegfr2 mais aussi par la voie du fgfr1 en liberant du fgf2 des matrices extracellulaires. Parmi dix composants de la matrice extracellulaire, nous avons pu identifier un site de retention commun pour le v189 et le fgf2, il s'agit du perlican. La presence de la sequence codee par l'exon 6 entraine donc la retention de v189 dans la matrice extracellulaire et lui confere la capacite d'agir indirectement par liberation d'autres facteurs basiques. Pour determiner les fonctions des recepteurs, nous avons developpe des anticorps anti-idiotypes du vegf. Nous avons obtenu des agonistes specifiques du vegfr2. In vitro, ces anticorps induisent la phosphorylation du vegfr2, la proliferation mais pas la migration des cellules endotheliales. In vivo, ils stimulent l'angiogenese tumorale sans affecter les cellules endotheliales quiescentes. Dans un modele d'angiogenese corneenne les anti-idiotypes induisent une reponse angiogenique meme en absence de vegf. Ces resultats permettent d'identifier le vegfr2 comme etant un marqueur fonctionnel de cellules endotheliales engagees dans un processus angiogenique. La conversion phenotypique des cellules endotheliales semble independante du vegf lui-meme.
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Benke, Emily Marie. "Role of VEGF-C in Proliferation and Migration in a Cancer Model". VCU Scholars Compass, 2008. http://scholarscompass.vcu.edu/etd/1533.
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Head and neck cancer ranks high among the most common cancers world wide. In addition, there is a high recurrence rate, as well as a high prevalence of loco-regional tumor spread. Among many factors contributing to metastasis is vascular endothelial cell growth factor C. VEGF-C is primarily an inducer of new lymph vessel formation, typically during embryogenesis; however, some advanced cancers show a significant increase in VEGF-C expression, suggesting a role in metastasis. In the current study, the effects of VEGF-C expression were tested in HN12 cells, which are highly metastatic and known to express high levels of the chemokine CXCL5. A connection between VEGF-C and CXCL5 expression was made in previous studies. VEGF-C expression was downregulated or upregulated in appropriate target cells, in order to test its effect on proliferation and migration. Downregulation of VEGF-C in HN12 cells resulted in a decrease in proliferation, migration and motility. Conversely, upregulation of VEGF-C in HN4 cells led to an increase in cell proliferation. In addition, downregulation of VEGF-C significantly lowered tumorigenicity in athymic mice. All results suggest VEGF-C is contributing to an increase in proliferation, migration and motility in this HNSCC model system.
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Matsumura, Kazuyoshi. "Modulation of VEGFR-2-mediated endothelial-cell activity by VEGF-C/VEGFR-3". Kyoto University, 2003. http://hdl.handle.net/2433/148461.
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Decio, Alessandra Agnese. "The VEGFC/VEGFR3 pathway in the malignancy of ovarian carcinoma". Thesis, Open University, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.606839.
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Vascular endothelial growth factor C (VEGFC) promotes tumor progression in several tumor types, mainly through the stimulation of lymphangiogenesis and lymphatic metastasis. The expression and biological significance of the VEGFCNEGFR3 pathway in ovarian cancer growth and dissemination has been investigated in this thesis using ovarian carcinoma cell lines and tumor animal models. In patient-derived ovarian carcinoma xenografts (HOC), high levels of soluble VEGFC in ascites and serum were detected, in association with disease progression and tumor burden. Peak VEGFC expression preceded para-aortic lymph node infiltration by HOCS neoplastic cells. Histological detection of tumor cells in blood and lymphatic vessels indicated both hematogenous and lymphatic dissemination. VEGFC was over-expressed in the VEGFR3-positive and luciferase-expressing lA9 and IGROVl ovarian cancer cells. In vitro. VEGFC released by the expressing turnor cells stimulated turnor cell migration in an autocrine manner. In vivo, over-expression of VEGFC promoted . IGROVl dissemination after orthotopic intraovarian transplantation in nude mice. VEGFC released in serum of mice correlated with tumor burden and metastasis. Cediranib, a small molecule receptor tyrosine kinase inhibitor of VEGFRl-3 and c-Kit, inhibited in vivo metastasis of VEGFC-overexpressing [GROVI and in vitro autocrine effects on turnor cell migration; cediranib improved the survival of mice bearing the four HOC xenografts analyzed. The therapeutic benefit was proportional to soluble VEGFC levels in serum and ascites and to VEGFR3 expression by tumor cells. Different schedules of cediranib were tested on HOC8 xenograft, The survival benefit of cediranib in maintenance regimen (14 weeks) was superior to 3-weeks treatment. A significant prolongation of mice survival was observed in mice treated with advanced turnor. Treatment benefits were improved combining cediranib with chemotherapy (paclitaxel plus cisplatin). These findings suggest that the VEGFCNEGFR3 pathway acts as an enhancer of ovarian cancer progression through autocrine and paracrine mechanisms, hence offering a potential target for therapy.
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Silva, Luciana Oliveira da. "Expressão do fator de crescimento endotelial vascular (VEGF) e seus receptores VEGFR-1 e VEGFR-2 durante o início da gestação em camundongos". Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/42/42134/tde-09092008-114452/.
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Em roedores, o aumento da permeabilidade vascular, a transformação decidual, e angiogênese são eventos cruciais para o sucesso da gestação. O fator endotelial vascular (VEGF) é um mitogênico para células endoteliais e um indutor de angiogênese. O VEGF age via dois receptores da família das tirosina quinases: VEGFR1 e VEGFR2. O objetivo deste estudo foi investigar usando o método imunohistoquímico, a expressão espacial e temporal do VEGF e os receptores VEGFR1 e VEGFR2 em células endometriais de camundongo entre o 4º e 8º dias de gestação. No 4º dia de gestação, VEGF, VEGFR1 e VEGFR2 foram expressos pelo epitélio luminal e glandular e fracamente pelo estroma endometrial. Do 5º ao 8º dias de gestação, o VEGF foi expresso nas células deciduais mesometriais. VEGFR1 e VEGFR2 foram expresso pelas células do epitélio luminal e glandular e mostraram uma marcação diferencial na decídua mesometrial e antimesometrial. Os receptores VEGFR1 e VEGFR2 foram intensamente expressos pelas células endoteliais dos capilares sinusóides mesometriais e pelas células Nk uterinas.In rodents, increase of vascular permeability, decidual cell transformation, and uterine angiogenesis are crucial events for the success of pregnancy. Vascular endothelial growth factor (VEGF) is a mitogen for endothelial cells and an inducer of angiogenesis. VEGF acts via two tyrosine kinase family receptors: VEGFR1 and VEGFR2. The aim of this study was to investigate using the immunohistochemical method, the spatiotemporal expression of VEGF and its receptors VEGFR1 e VEGFR2 by mouse endometrial cells on days 4 to 8 of pregnancy. On day 4, VEGF, VEGFR1 and VEGFR2 were expressed mostly by the luminal and glandular epithelium. Stromal cells showed a very weak labeling. On days 5-8, VEGF and its receptors showed an increased labeling throughout the mesometrial decidua. The expression of VEGF, VEGFR1, and VEGFR2 were differentially expressed in the mesometrial cells and in the predecidual cells of the antimesometrial decidua. VEGFR1 and VEGF R2 were highly expressed by endothelial cells of the mesometrial sinusoids, and Nk uterine cells.
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Guimarães, Carina de Fátima. "Expressão de VEGF (VEGFR1/VEGFR2) e avaliação estereológica da membrana corioalantóide a termo em éguas Puro Sangue Inglês: influência da pluriparidade sobre o peso dos potros ao nascimento". Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/10/10131/tde-19022014-115000/.
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A interação materno fetal na espécie equina depende exclusivamente da complexidade anatômica e fisiológica da placenta e este órgão endócrino provisório é a peça chave do presente estudo, onde objetivou-se avaliar a influência do número de partos sob a eficiência placentária. Buscando, por meio da morfometria das macro e microrregiões, além da expressão do VEGF, VEGFR-1/Flt-1 e VEGFR-2/FLK-1 na membrana corioalantóide a termo, dados referentes à inter-relação da pluriparidade, contato materno fetal e peso dos neonatos da raça Puro Sangue Inglês. O delineamento experimental consistiu em um estudo analítico, observacional, transversal, prospectivo. Foram acompanhados cinquenta partos de éguas divididas em três grupos de acordo com a pluriparidade: primíparas (n=18), 2 a 5 partos (n=14) e 6 a 10 partos (n=18). Foram coletados e fixados em formol fragmentos de 3 cm2 das regiões do corpo do útero (Cut), corno uterino gestante (CG) e corno uterino contralateral (CnG) da membrana corioalantóide a termo pós delivramento. Após processamento foram corados pela técnica de Hematoxilina & Eosina e Picro-Sirus-Red. Os estudos imunohistoquímico (método avidina-biotina) e esterológico foram realizados ao microscópio óptico. Foram correlacionados número de partos, altura e perímetro torácico (PT) maternos; idade, altura e PT paternos; composição volumétrica dos compartimentos placentários juntamente com as áreas de superfície de contato materno-fetal e peso, altura e escore de vitalidade neonatal. A paridade, além de diretamente relacionada ao peso do neonato, demonstrou na avaliação morfofuncional ser determinante ao ganho de eficiência placentária. As membranas corioalantóides das éguas pluríparas tenderam a apresentar maior volume total no CG, aumento na porcentagem e volume total de vilos, além de maior densidade microcotiledonária e expressão do VEGF na região do CG. Entre as muitas correlações determinadas no grupo primíparas as mais relevantes foram peso da membrana com variáveis neonatais como peso (r=0,598), PT (r=0,775), tempo para mamar (r=0,553) e tempo de gestação (r=-0,527), além do PT da mãe com o tempo para ruptura do cordão umbilical (r=0,564), reflexo de sucção (r=0,625), para levantar (r=0,756) e decúbito esternal (r=-590). Da mesma forma no grupo 2 a 5 partos, neonatos que nasceram com maior peso, altura, e PT apresentaram menor tempo para levantar (r=-0,546; r=-0,869, r=-0,892), eliminação do mecônio (r=-0,535) e ruptura do cordão umbilical (r=-0,528; r=-0,881). Assim como no grupo 6 a 10 partos, o peso do potro apresentou correlação com o peso (r=0,793), PT (r=0,716) e altura (r=0,667) materna. O volume total do CG correlacionou com volume total do parênquima (r=-0,816) e epitélio nos vilos placentários do CG (r=-0,915), tempo de gestação (r=-0,483), tempo para reflexo de sucção (r=-0,672), para mamar (r=-0,525), e para eliminação do mecônio (r=-0,525). No que diz respeito às variáveis paternas, o peso paterno correlacionou com o volume total do parênquima nos vilos placentários do CnG (r=0,393) , além do PT do garanhão com o peso (r=0,316) e PT (r=0,425) do potro e volume total do CG (r=0,319). Desta forma, acredita-se que estes resultados possam fornecer ferramentas práticas para auxiliar na escolha das fêmeas e machos mais indicados para geração de potros neonatos com desenvolvimento adequado.Fetomaternal interaction in equine species depends exclusively on the complexity of placental anatomy and physiology. This transient endocrine organ is the key of the present study, which aimed to evaluate the influence of parity on placental efficiency. Morphometric of macro and micro regions, expression of VEGF, VEGFR-1/Flt-1 and VEGFR-2/FLK-1 in term corioallantois were performed and data regarding parity, fetomaternal contact and neonatal weight were evaluated in Thoroughbred. The experimental study consisted of an analytical, observational, cross-sectional, prospective study. Fifty deliveries were monitored in mares divided into three groups according to parity: nulliparous (n=18), 2 to 5 deliveries (n=14) and 6 to 10 deliveries (n=18). Tissue sections measuring 3 cm 2 were collected and fixed in formol saline from term chorioallantois regions: uterine body (UtB), pregnant uterine horn (PH) and contralateral uterine horn (CtH). After processing, samples were stained using Hematoxylineosin and Picro-Sirus-Red. Imunnohistochemistry (avidin-biotin method) and stereology were performed using an optic microscope. Correlations between parity, maternal height and thoracic perimeter; paternal age, height and thoracic perimeter; volume composition of placental compartments, surface area of fetomaternal contact and weight, height and neonatal vitality score were performed. Parity was directly related to weight of the neonate and demonstrated in morphofunctional evaluation to be determinant for placental efficiency. Chorioallantoic membranes from pluriparous mares tended to have greater total PH volume, higher percentage and total villi volume, and greater microcotiledonary density and VEGF expression in PH region. There were several correlations found in nulliparous group, the most relevant were membrane weight and neonatal parameters such as weight (r=0,598), thoracic perimeter (r=0,775), time to nurse (r=0,553) and gestational length (r=-0,527) and also mares thoracic perimeter with time to rupture the umbilical cord (r=0,564), suckle reflex (r=0,625), time to stand (r=0,756) and to achieve sternal recumbency (r=-590). Likewise, for the 2 to 5 deliveries group, neonates that were born heavier, taller and with greater thoracic perimeter took less time to stand (r=-0,546; r=-0,869, r=-0,892), pass meconium (r=-0,535) and rupture the umbilical cord (r=-0,528; r=-0,881). In the group of mares between 6 and 10 deliveries, foals weight was correlated to maternal weight (r=0,793), thoracic perimeter (r=0,716) and height (r=0,667). Total PH volume correlated to total parenchyma (r=-0,816) and epithelium in placental villi in PH (r=-0,915), gestational lenght (r=-0,483), time to suckle reflex (r=- 0,672), to nurse (r=-0,525), and pass meconium (r=-0,525). Regarding Paternal variables, paternal weight correlated to total parenchyma volume in placental villi of the CtH (r=0,393). Also thoracic perimeter of the stallion correlated to neonatal weight (r=0,316) thoracic perimeter (r=0,425) and total volume of the PH (r=0,319). Therefore, these data provides rationale for an adequate choice of mares and stallions to generate well-developed neonates.
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Schmidt, Augusto Frederico Santos. "Efeiro do tratamento pré-natal com ácido retinóico na expressão pulmonar de VEGF e seus receptores VEGFR1 e VEGFR2 no modelo animal de hérnia diafragmática congênita induzida pelo nitrofen". [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310453.
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Orientador: Lourenço Sbragia NetoTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: A hérnia diafragmática congênita (HDC) é uma doença grave com alta mortalidade devido à hipoplasia e hipertensão pulmonar. A via do ácido retinóico tem sido implicada na patogênese da HDC e pode ser uma alternativa de intervenção na promoção da alveolarização e vascularização pulmonar. O fator de crescimento vascular do endotélio (VEGF - Vascular Endothelial Growth Factor) e seus receptores VEGFR1 e VEGFR2 têm importante função no crescimento e na vascularização pulmonar, e, possivelmente, na patogênese da HDC. No entanto, não se conhece como o tratamento pré-natal com ácido retinóico pode afetar a vascularização pulmonar e seus fatores de crescimento. O objetivo deste estudo foi analisar o efeito do tratamento pré-natal com ácido retinóico na vascularização pulmonar e na expressão pulmonar de VEGF e seus receptores VEGFR1 e VEGFR2 em fetos de rato com HDC induzida pelo nitrofen (2,4-dicloro-4'nitrodifenil éter). Fetos de ratas Sprague-Dawley prenhes foram divididos em oito grupos: 1) controle externo, 2) placebo óleo nitrofen; 3) placebo óleo ácido retinóico, 4) tratados com ácido retinóico, 5) expostos ao nitrofen sem HDC, 6) expostos ao nitrofen com HDC, 7) expostos ao nitrofen sem HDC e tratados com ácido retinóico, 8) expostos ao nitrofen com HDC e tratados com ácido retinóico. Nitrofen foi administrado por via oral (gavagem) com 9,5 dias de gestação. Ácido retinóico foi administrado por via intraperitoneal com 18,5, 19,5 e 20,5 dias de gestação na dose de 5 mg/kg/dia, a coleta fetal foi realizada com 21,5 dias (termo=22 dias). Cada grupo fetal foi composto por 25 fetos. As variáveis morfológicas estudadas foram: peso corporal (PC), peso pulmonar total (PPT), peso do pulmão esquerdo (PPE) e a relação peso pulmonar total / peso corporal (PPT/PC). A morfologia pulmonar foi estudada pela mensuração da média linear de interceptação (MLI) e seus componentes diâmetro interno dos espaços aéreos (DEA) e a relação de comprimento de transecção do parênquima / espaço aéreo (MCTP). A morfologia vascular foi estudada pela mensuração do diâmetro externo (DE), diâmetro interno (DI) e espessura proporcional da camada muscular média (ECM) de arteríolas pulmonares de resistência. A expressão de VEGF e dos receptores VEGFR1 e VEGFR2 foi analisada por meio de imunoistoquímica e western blotting. Os dados morfológicos e morfométricos foram analisados pelo teste ANOVA com pós-teste de Tukey-Kramer, a avaliação semiquantitativa da imunoistoquímica foi analisada pelo teste de Kruskal-Wallis com pós-teste de Dunn, sendo considerados significativos valores de p<0,05 para ambos os testes. A freqüência de HDC observada entre os fetos expostos ao nitrofen foi de 40%. As variáveis morfológicas apresentaram diminuição significativa nos grupos expostos ao nitrofen, especialmente nos fetos com HDC (p<0,05). O tratamento com ácido retinóico não alterou as variáveis morfométricas pulmonares. Fetos com HDC apresentaram aumento da ECM, enquanto o tratamento com ácido retinóico reduziu a ECM nos fetos com HDC (p<0.001). A presença de HDC levou à diminuição da expressão de VEGF, VEGFR1 e VEGFR2, enquanto o tratamento com ácido retinóico recuperou a expressão de VEGF e VEGFR1. A alteração sinalização da via do VEGF na HDC pode estar associada à patogênese da hipoplasia e da hipertensão pulmonar. O tratamento pré-natal com ácido retinóico pode fornecer vias para tratamento da hipertensão pulmonar na HDC por meio da redução da ECM das arteríolas pulmonares e recuperação do VEGF e seus receptores
Abstract: Congenital diaphragmatic hernia (CDH) is a life-threatening disease with high mortality due to the pulmonary hypertension and hypoplasia. Vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2 play a major role in lung vascularization, growth, and possibly in the pathogenesis of CDH. However it is not know how prenatal treatment with retinoic acid can affect lung vascularization by acting on the VEGF signaling. The purpose of this study was to analyze the effect of antenatal retinoic acid treatment on the expression of pulmonary VEGF and its receptors VEGFR-1 and VEGFR-2 in rat fetuses with CDH induced by nitrofen. Fetuses from pregnant Sprague-Dawley rats (term=22 days) were divided in eight groups: 1) external control, 2) placebo oil nitrofen, 3) placebo oil retinoic acid, 4) treated with retinoic acid, 5) exposed to nitrofen without CDH, 6) exposed to nitrofen with CDH, 7) exposed to nitrofen without CDH and treated with retinoic acid, 8) exposed to nitrofen with CDH and treated with retinoic acid. Nitrofen (2,4- dichloro-4'-nitrodiphenyl ether) was administered by gavage (100 mg) at 9,5 days of gestation. Retinoic acid was administered intraperitoneally on days 18.5, 19.5 and 20.5 of gestation (5 mg/kg), harvest was performed at 21.5 days (term =22 days). Each fetal subgroup was composed of 25 fetuses. The morphologic variables studied were: body weight, total lung weight, left lung weight, and total lung weight to body weight ratio. Pulmonary morphometry was studied by measuring the mean linear intercept and its components: internal diameter of airspaces and mean transection length / airspace. Vascular morphometry was studied by measuring the external diameter, internal diameter and proportionate thickness of the medial muscular layer of pulmonary resistance arterioles. Immunohistochemistry and Western blotting analysis were used to assess VEGF, VEGFR-1 and VEGFR-2 expression. Data was analyzed using ANOVA with Tukey's post-test and immunohistochemistry was studied semiquantitatively using Kruskal-Wallis test with Dunn's post-test. The frequency of CDH was 40%. The morphological variables showed reduction in the nitrofen group with and without CDH, which were more pronounced in the latter (p<0.05). Retinoic acid did not affect fetal morphology. There was no difference in pulmonary morphometry among groups. Fetuses with CDH had increased proportionate thickness of the medial muscular layer of pulmonary arterioles, while treatment with retinoic acid reduced this variable in fetuses with CDH (p<0.001). Fetuses with CDH had reduced VEGF, VEGFR1 and VEGFR2 expression, while retinoic acid treatment restored expression VEGF and VEGFR1. VEGF signaling disruption may be associated with pulmonary hypertension in CDH. Retinoic acid may provide a pathway for acting on pulmonary hypertension by reducing medial thickness of pulmonary arterioles and restoring expression of VEGF and its receptors
Doutorado
Cirurgia
Doutor em Ciências da Cirurgia
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Veikkola, Tanja. "Dissecting VEGFR-2 and VEGFR-3 function : VEGFR-3 mediates lymphangiogenic signals". Helsinki : University of Helsinki, 2002. http://ethesis.helsinki.fi/julkaisut/mat/bioti/vk/veikkola/.
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Kranich, Sandra [Verfasser]. "Effekte der Wachstumsfaktoren VEGF-C und VEGF-D und Signaltransduktion des Rezeptors VEGFR-3 in Zellen des zentralen Nervensystems / Sandra Kranich". Kiel : Universitätsbibliothek Kiel, 2009. http://d-nb.info/1019868597/34.
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Reille-Seroussi, Marie. "Système VEGF/VEGFR : conception et évaluation de molécules ciblées et régulation potentielle par les métaux". Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05P614/document.
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Dans les thérapies anticancéreuses, les traitements anti-angiogéniques agissant sur l’axe VEGF/VEGFR ont une place importante en clinique. Dans ce contexte, nous avons conçu et évalué l’activité de nouveaux inhibiteurs de l’interaction VEGF/VEGFR. Une première approche a été la conception de molécules antagonistes du VEGFR1. Différents analogues hétérocycliques dérivant d’un composé de type (3-carboxy-2-ureido) thiophène ont été synthétisés. Des réactivités chimiques intéressantes ont été mises en évidence, mais l’activité biochimique de ces molécules ne s’est pas révélée concluante. Une seconde approche reposant sur la conception de peptides ciblant le VEGF a alors été initiée. A partir d’un peptide cyclique connu de 19 résidus ayant une affinité submicromolaire pour le VEGF, de nouveaux peptides et peptidomimétiques ont été développés.L’objectif a été de concevoir des composés de structures chimiques potentiellement plus simples et plus stables en milieu biologique, tout en optimisant l’affinité pour le VEGF. L’interaction de ces peptides avec le VEGF a été étudiée in vitro par ELISA et ITC, ainsi que par cristallographie pour le composé le plus affin. En parallèle, nous avons étudié l’effet du cuivre et d’autres métaux divalents sur l’interaction VEGF/VEGFR1. Au travers d’expériences réalisées au laboratoire ainsi qu’en collaboration, nous avons montré que certains métaux étaient capables non seulement d’inhiber l’interaction VEGF/VEGFR1 mais également d’induire une dimérisation non classique du domaine 2du récepteur. Sachant que les métaux, et en particulier le cuivre, sont connus pour jouer un rôle important dans l’angiogenèse, cette découverte apporte de nouveaux éléments de réponse sur leur mécanisme d’action. Ce travail de thèse s’inscrit donc non seulement dans une démarche de développement de nouveaux composés anti-angiogéniques mais également de compréhension du mécanisme de régulation de l’angiogenèseInhibiting angiogenesis is an effective strategy of targeting therapy against cancer. In thiscontext, we develop an antiangiogenic strategy consisting in the design and evaluation of compoundsblocking the VEGF/VEGFR interaction. The first approach was the conception of antagonists of theVEGFR1. Starting from a (3-carboxy-2-ureido) thiophene hit, a variety of heterocyclic analogs wasdeveloped. Interesting chemical observations were made during the synthesis, but no optimization ofthe biochemical activity was achieved. The second approach was the design of peptides that bind tothe receptor-recognition surface of the VEGF. Starting from a cyclic peptide known to bind to theVEGF with a sub-micromolar affinity, new peptides and peptidomimetics were developed. Thestrategy was to design simplified and potentially more stable compounds, and to improve at thesame time the VEGF affinity. The interaction of VEGF with these ligands was studied in vitro by ELISAand ITC experiments, as well as X-ray diffraction for the best compound. Moreover, the investigationof the effects of copper and other divalent metals on the VEGF/VEGFR1 interaction was undertaken.Experiments realized in the laboratory and in collaboration showed that metals were able to displacethe VEGF/VEGFR1 interaction and to induce the dimerisation of the domain 2 of the receptor. Metalsare well known to play an important role in angiogenic phenomena, but their specific targets are stilla matter of debate. In this context, this discovery brings new response elements regarding theirmechanisms of action. Therefore, the objectives of this PhD thesis were the development of newantiangiogenic compounds, as well as the understanding of some aspects of the regulation of angiogenesis
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Olofsson, Birgitta. "Studies of the vascular endothelial growth factors, VEGFs, and their receptors, focusing on VEGF-B /". Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3633-1/.
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Homman, Ludiye Jihane. "Rôle et expression du facteur lymphangiogénique VEGF-C et de son récepteur VEGFR-3 au cours du développement du cerveau embryonnaire". Paris 6, 2008. http://www.theses.fr/2008PA066052.
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Le VEGF-C a été caractérisé pour son implication dans le développement des vaisseaux lymphatiques via l’activation de son récepteur à activité tyrosine kinase, VEGFR-3. Le VEGF-C liant également les récepteurs Neuropilines exprimés par les cellules neurales, nous avons examiné si les cellules neurales répondaient au VEGF-C et si elles exprimaient le VEGFR-3. J’ai d’abord montré, in vitro, que le VEGF-C stimule la prolifération des précurseurs neuraux exprimant le VEGFR-3 dans bulbe olfactif embryonnaire ainsi que la prolifération et la migration de précurseurs oligodendrocytaires du chiasma optique chez la souris. J’ai localisé par hybridation in situ les sites d’expression du Vegf-c et du Vegfr-3 dans les régions septo-hippocampale, pré-thalamique et dorso-latérale du thalamus du cerveau embryonnaire et adulte de poulet. En effet, le modèle de poulet est très utilisé pour ce genre de manipulation du fait de son accessibilité aux stades embryonnaires. J’ai ensuite généré et testé la validité d’une série d’outils moléculaires permettant de bloquer par ARN interférence l’expression du Vegfr-3 (siRNAs et shRNAs codé par un plasmide pouvant être électroporé ou dans un lentivirus capable d’infecter durablement le cerveau embryonnaire et adulte). J’ai mis au point la technique d’électroporation et permis d’engager les expériences d’ARN interférence actuellement en cours. J’ai également mis au point les analyses fonctionnelles permettant d’évaluer les effets de la perte de fonction du VEGFR-3 sur la prolifération, la survie, la mise en place des populations neuronales exprimant le gène codant le Vegfr-3 dans le septum et ainsi que sur le développement des projections axonales connectant l’hippocampe dans lequel le Vegf-c est exprimé.
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Gonçalves, Silvana Beltrami. "Efeito do VEGF na angiogênese pulpar e na apoptose". Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/25/25138/tde-22062007-094740/.
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O fator de crescimento vascular endotelial (VEGF) desempenha um papel importante na angiogênese, induzindo a proliferação da célula endotelial, migração e sobrevivência. Com o intuito de promover a formação de novos vasos, e obter uma melhora na circulação colateral, VEGF tem sido utilizado para o tratamento de áreas de isquemia cardíaca, na doença cardiovascular. A manutenção da vitalidade pulpar com VEGF pode melhorar o prognóstico dos dentes que sofreram avulsão, prevenindo a perda precoce do dente. O propósito deste estudo foi desenvolver um modelo para se estudar o processo de revascularização da polpa dentária e avaliar o efeito do VEGF- 165 na angiogênese da polpa humana e na apoptose. Fatias de dente humano foram mantidas in vitro (cultura) com e sem VEGF (50ng/ml) durante 7 dias. Coloração de imuno-histoquímica para o Fator de Von Willebrand (Fator VIII) foi utilizada para quantificar o número de vasos sangüíneos no tecido pulpar. O número de vasos sangüíneos foi significantemente mais alto no grupo do VEGF (média -67.87) comparado ao grupo controle (média- 46.25, p< .05). O teste do Tunel foi usado para determinar o número de células apoptóticas nos grupos com e sem VEGF. Análises da expressão de VEGFR-2 por RT-PCR foram realizadas nas células endoteliais da microvasculatura da derme humana (HDMECs), células pulpares indiferenciadas (OD-21), células tipo odontoblasto de camundongo (MDPC-23) e macrófagos. A expressão de VEGFR-2 foi detectada nas HDMECs, mas não nas outras 3 linhas celulares. Quatro fatias de dente humano por camundongo imunodeprimido foram implantadas na região dorsal, subcutaneamente, pelo período de 7 dias. A vitalidade pulpar foi determinada pelas análises microscópica e imuno-histoquímica. O teste do Tunel foi usado para determinar o número de células apoptóticas. O modelo de angiogênese pulpar utilizando camundongos imunodeprimidos (SCID mouse model of pulp angiogenese) demonstrou ser um modelo viável para se estudar o processo de revascularização da polpa dentária humana. Levando-se em consideração os resultados obtidos neste estudo, sugere-se que o VEGF possa ter um efeito positivo na revascularização de dentes avulsionados. E que o modelo de angiogênese pulpar desenvolvido nesta pesquisa possa ser útil para responder a inúmeras novas questões experimentais na área de Endodontia.The Vascular endothelial growth factor (VEGF) plays na important role in angiogenesis by inducing endothelial cell proliferation, migration, and survival. To promote new vessel formation and improve collateral circulation, VEGF has been used to treat ischemic heart areas in cardiovascular disease. Maintenance of pulp vitality with VEGF may improve the outcomes of avulsed teeth, preventing premature tooth loss. The purpose of this study was to develop a model system to study the process of dental pulp revascularization, and assess the effect of VEGF-165 in the human pulp angiogenesis and apoptosis. Human tooth slices were maintained in vitro for 7 days +/- VEGF (50ng/mL). Immunohistochemistry staining for Von Willebrand?s factor (Factor VIII) was used to quantify the number of vessels in pulp tissues. There was a significantly higher number of blood vessels in the VEGF group (67.8 Mean) compared to the control group (46.2 Mean, p<0.05). Tunel Assay was used to determine the number of apoptotic cells in +/- VEGF groups. RTPCR analyses of VEGFR-2 transcripts were used on human dermal microvascular endothelial cells (HDMECs), undifferentiated pulp cells (OD-21), mouse odontoblast-like cells (MDPC-23), and macrophages. VEGFR-2 expression was detected in HDMECs but not in the other 3 cell lines. Four tooth slices per mouse were subcutaneously implanted in the dorsal region for 7 days. Pulp vitality was determined by histological and immunohistochemical analysis. Also, Tunel Assay was used to determine the number of apoptotic cells. SCID mouse model of pulp angiogenesis demonstrated to be a good model system to study revascularization of human dental pulps. Taking into account the findings of this study, it is suggested that VEGF could have a positive effect in the revascularization of avulsed teeth. It is hoped that this pulp angiogenesis model be useful to answer a number of new experimental questions in the area of Endodontics.
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Sentilhes, Loïc. "Etudes in vivo de l'ontogénèse des systèmes VEGF/ VEGFR-2 et fibrinolytiques et applications à l'ischémie cérébrale périnatale". Rouen, 2010. http://www.theses.fr/2010ROUENR01.
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Les objectifs étaient d'étudier (i) la distribution temporo-spatiale du V EGF et VEGFR-2 par dans le cerveau et le cervelet humain normal ainsi que dans le cerveau humain ayant subi une hypoxie-ischémie, à différents âges gestationnels; (ii) le système fibrinol\Zique à la naissance en fonction de l'âge gestationnel de naissance des nouveaux-nés. Les résultats ont montré que (i) VEGF est impliqué dans plusieurs aspects du développement des cellules neurales (migration, différenciation, synaptogénèse, myélination), et que VEGFR-2 pourrait être un des principaux récepteurs médiant ces actions; (ii) VEGF joue un rôle central (non medié par VEGFR-2) dans les régions du télencéphale humain exposées à l'ischémie en période prénatale; (iii) les prématurissimes développent dans les 10 premiers jours de vie un état antifibrinolytique, qui pourrait être un des facteurs de risque possible de survenue d'infarcissement périventriculaire hémorragique chez ces enfantsThe objectives were (i) to investigate the temporo-spatial distribution of the VEGUVEGFR-2 signalling pathway in the human forebrain and cerebellum and in the human ischemic forebrain at several developmental stages; (ii) to compare the fibrinolytic system at birth of extremely preterm, very preterm, and moderately preterm neonates to that of full-term neonates. The results showed that (i) VEGF is involved in several aspects of neural cell development -migration, differentiation, synaptogenesis and myelination - and that VEGFR-2 might be one of the main receptors that médiate these properties; (ii) VEGF plays roles which are unlikely to be mediated by VEGFR-2 in the human forebrain régions exposed to ischemia during the pré- and neonatal period; (iii) the development within 10 days alter the birth of extremely preterm infants of fibrinolysis suppression, which may contribute te, the increased risk of periventricular hemorrhagic infarction in this gestational-age group
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Samikannu, Balaji [Verfasser]. "Dipeptidyl Peptidase IV inhibition activates CREB and improves islet vascularization through the VEGF-A/VEGFR-2 pathway / Balaji Samikannu". Gießen : Universitätsbibliothek, 2013. http://d-nb.info/1065065426/34.
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Volkmer, Anne Kathrin [Verfasser]. "Regulation des VEGF-Systems in endometrialen Stromazellen : Untersuchungen zur mRNA-Expression der Rezeptoren VEGFR1 und sFlt-1 / Anne Kathrin Volkmer". Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2011. http://d-nb.info/1015434991/34.
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Mao, Kaili. "Rôle du Vascular Endothelial Growth Factor-A (VEGF-A) et de son récepteur VEGFR-1 dans le cancer prostatique localisé". Thesis, Paris Est, 2008. http://www.theses.fr/2008PEST0041/document.
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Ce travail a analysé l’expression du facteur de croissance angiogénique, le VEGF-A, et de son récepteur VEGFR-1, dans le cancer prostatique localisé. Dans la première partie, nous avons mesuré le taux plasmatique de VEGF-A chez 100 patients opérés d’un cancer prostatique localisé. Nous avons également mesuré l’expression tissulaire du VEGF-A sur les pièces opératoires. Il n’y avait pas d’association entre le VEGF-A plasmatique et les facteurs pronostiques du cancer prostatique. Cependant, l’expression du VEGF-A était corrélée au score de Gleason (p=0,01). Dans la deuxième partie, la même cohorte de patients a été utilisée. L’expression tissulaire du VEGFR-1 a également été mesurée. Les patients ont été suivis avec des dosages réguliers du PSA. Durant le suivi, 14 patients ont eu une récidive biologique. Ni le taux plasmatique de VEGF-A (p=0,25), ni l’expression tissulaire du VEGF-A (p=0,38), ni l’expression tissulaire du VEGFR-1 (p=0,34) n’étaient associés au risque de récidive biologique. Dans la troisième partie, nous avons mesuré l’expression tissulaire du VEGF-A et du VEGFR-1 sur les pièces opératoires de 40 patients opérés d’un cancer prostatique localisé. L’expression tissulaire du VEGF-A était significativement plus importante chez les patients ayant eu une progression tumorale après l’intervention que chez les patients n’ayant pas récidivé (p=0,046). En revanche, celle du VEGFR-1 était identique dans les deux groupes. L’expression tissulaire du VEGF-A était le facteur prédictif de progression tumorale le plus significatifThis study analysed the expression of angiogenic growth factor, VEGF-A and its receptor, VEGFR-1 in localized prostate cancer. In the first part, we measured the plasma levels of VEGF-A in 100 patients operated with radical prostatectomy for clinically localized prostate cancer. We also measured the tissue expression of VEGF-A using ELISA on the surgical specimen. There were no associations between plasma levels of VEGF-A and the usual prognostic factors of prostate cancer. However, the tissue expression of VEGF-A correlated with Gleason score (P = 0.01). In the second part, we used the same patients group. Patients were prospectively followed with regular PSA determinations.14 patients had a biochemical recurrence. Neither plasma level of VEGF-A (P =0.25) nor tissue expression of VEGF–A (P=0.38) and its receptor VEGFR–1 (p=0,34) were associated with the risk of biochemical recurrence after radical prostatectomy. Finally, we measured the tissue expression of VEGF-A and VEGFR-1 on the surgical specimens of 40 patients who underwent radical prostatectomy for clinically localized prostate cancer. The tissue expression of VEGF-A in patients who experienced progression was significantly higher than in those who remained free of recurrence (P=0.046). However, the expression of VEGFR-1 was similar in both groups. In logistic analysis, the expression of VEGF-A was the most significant predictor of tumor progression. These results suggest that the tissue expression of VEGF-A has a prognostic impact in clinically localized prostate cancer
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Mao, Kaili Dinh-Xuan Anh-Tuan. "Rôle du Vascular Endothelial Growth Factor-A (VEGF-A) et de son récepteur VEGFR-1 dans le cancer prostatique localisé". S. l. : Paris Est, 2008. http://doxa.scd.univ-paris12.fr:80/theses/th0494618.pdf.
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Jeltsch, Michael. "VEGFR-3 ligands and lymphangiogenesis". Helsinki : University of Helsinki, 2002. http://ethesis.helsinki.fi/julkaisut/mat/bioti/vk/jeltsch/.
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Sjöström, Sara. "Risk and prognostic factors for malignant glioma". Doctoral thesis, Umeå universitet, Onkologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-61905.
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Background: Glioblastoma is the most common and aggressive type of glioma and associated with poor prognosis. Apart from ionizing radiation and some rare genetic disorders, few aetiological factors have been identified for primary brain tumours. Inverse associations to asthma and low IgG levels for varicella zoster virus have in previous studies indicated that the immune system may play a role in glioma development. Little is known about prognostic factors in glioma. Previous studies have shown an association between age, Karnofsky performance status, O6-methylguanine-DNA methyltransferase (MGMT) hypermethylation, and prognosis. Polymorphisms in different low penetrance genes have in some studies been associated with glioma prognosis. Material and methods: In paper I, we analysed IgG levels for four different viruses, Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella zoster virus (VZV) and adenovirus (Ad), in prediagnostic blood samples from 197 cases with glioma and 394 controls collected from three large cohorts: the Northern Sweden Health and Disease Study; the Malmö Diet and Cancer Study; and the Diet, Cancer and Health cohort from Copenhagen. ELISA was used to measure IgG levels and for EBV response to both the nuclear antigen (EBNA1) and the viral capsid antigen (VCA) was measured, for VCA using immunoflourescence. IgG levels were divided into quartiles and binary logistic regression was used to compare the quartiles in cases and controls. All odds ratios were adjusted for age, sex, and cohort. In paper II-IV, we studied 176 glioblastoma cases from Sweden and Denmark. We collected treatment and follow-up data on the cases. We genotyped 30 tagging SNPs in EGF, 89 in EGFR, 27 in VEGFR2, and 17 in VEGF. We also studied 1458 SNPs in 136 DNA repair genes. Hazard ratios were calculated using Cox regression; the major allele was set as categorical variable and all HR were adjusted for age, sex, country, and treatment. For the DNA repair gene results, we adjusted the p-values for multiple testing. Significant findings were confirmed in separate datasets. Results and Discussion: We found a trend towards higher IgG VZV levels in controls compared to glioma cases, especially when restricting the analyses to only include glioma cases with at least 2 years between blood sample and diagnosis. This finding might indicate that there is an aetiological and not a disease-related association. This confirms previous findings and support that a strong immune system can detect and inhibit growth of small cancer clusters. In EGF, we found seven SNPs in one haplotype block that were significantly associated with glioblastoma survival. Four of the SNPs were available for confirmation; however, none reached statistical significance. One explanation could be age differences in the different cohorts. In EGFR, four SNPs associated with survival were found; however, as 89 polymorphisms were tested this was the expected outcome by chance. In VEGF and VEGFR2, we found two SNPs associated with glioblastoma survival, but they could not be confirmed in the separate dataset, and due to multiple testing, were considered to be false positives. Among the DNA repair genes, we found nine SNPs in three genes-MSH2, RAD51L1 and RECQL4-associated with glioblastoma survival after confirmation and adjustment for age, sex, country, and treatment. After adjusting for multiple testing, one SNP in MSH2 and one in RECQL4 remained significant. Conclusions: Our studies provide additional knowledge to the aetiological and prognostic factors important for glioma, emphasising the possible importance of immune function mechanisms. We found limited evidence for the role of genetic variants in glioma progression genes, and some for DNA repair variants as prognostic factors for glioblastoma survival.
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Dias, Fernando José. "Influência de densidades do laser de baixa intensidade sobre o músculo masseter de ratos Wistar". Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/58/58137/tde-12082010-150530/.
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A laserterapia tem sido muito utilizada como tratamento alternativo em pacientes com dores crônicas relacionadas às disfunções temporomandibulares. Isso se deve aos efeitos: analgésico, antiinflamatório, miorrelaxante, de redução da fadiga durante as contrações tetânicas, aumento da força de mordida e diminuição da dor orofacial. Embora sejam observados resultados clínicos, ainda não é bem compreendido o seu efeito em nível celular. Assim, este estudo tem como objetivo analisar os efeitos das diferentes densidades (doses) de irradiação do laser de baixa intensidade (LLLI), em nível celular, sobre o músculo masseter de ratos Wistar. Os animais foram alocados aleatoriamente em 6 grupos (n=10), receberam 10 irradiações do laser (GaAlAs,780nm, 5mW e spot 0,04cm²) sobre o músculo masseter esquerdo variando a densidade de energia (I. 0; II. 0,5; III. 1,0; IV. 2,5; V. 5,0 e VI. 20 J/cm²). Após as 10 irradiações os músculos masseteres foram obtidos dos animais sob anestesia para análises: 1. Histoenzimológicas para atividade da nicotinamida adenina dinucleotídeo diaforase(NADH), succinato desidrogenase (SDH) e adenosina trifosfatase (ATPase), 2. Microscopia de luz (HE), 3. Microscopia eletrônica de transmissão e 4. Imunohistoquímica para fator de crescimento do endotélio vascular (VEGF) e o receptor 2 para VEGF (VEGFR-2). A atividade do NADH nos grupos IV, V e VI (30±1,26; 33,47±2,15; 31,67±1,77 - fibras intermediárias) apresentou um aumento significativo (p>0,05) no metabolismo oxidativo em relação aos demais grupos. Na atividade do SDH, o aumento foi discreto, com aumento significativo (p>0,05), apenas no grupo V (32,2±1,61 fibras intermediárias), com o padrão de aumento metabólico muito parecido nas reações de NADH e SDH. A atividade da ATPase não revelou diferenças entre os grupos tanto em meio ácido como no alcalino. A microscopia de luz revelou fibras musculares arredondadas e núcleos periféricos achatados, os quais tornaram mais arredondados com as densidades maiores de energia. Ultraestruturalmente as irradiações com as maiores densidades de energia revelaram mitocôndrias de tamanhos e formas variadas e cisternas do retículo sarcoplasmático dilatadas entre as miofibrilas. As análises qualitativas mostraram um padrão de aumento a expressão do VEGF e VEGFR-2 proporcionais à densidade de energia do laser usada. Conclui-se que o laser com densidades maiores foi capaz de aumentar o metabolismo oxidativo, sem alterar a capacidade contrátil, aumentar o volume do núcleo, modificar a ultraestrutura das fibras musculares e as expressões do VEGF e VEGFR-2.The laser therapy has been widely used as an alternative treatment in patients with chronic pain related to temporomandibular disorders. This is due to the effects: analgesic, anti inflammatory, muscle relaxant, reducing fatigue during tetanic contractions, increased bite strength and decrease in orofacial pain. Although clinical results are observed, is not well understood its effect on the cellular level. This study aims to analyze the effects of different densities (doses) irradiation of low level laser therapy (LLLI) on cellular level, on the masseter muscle of rats. The animals were randomly assigned to 6 groups (n=10), received 10 laser irradiation (GaAlAs, 780nm, 5mW spot and 0.04 cm²) on the left masseter muscle by varying the energy density (I. 0; II. 0.5; III. 1.0; IV. 2.5; V. 5.0 and VI. 20 J/cm²). After 10 irradiations the masseter muscles were obtained from animals under anesthesia for analysis: 1. Histoenzimologic for nicotinamide adenine dinucleotide (NADH), succinate dehydrogenase (SDH) and adenosine triphosphatase (ATPase), 2. Light microscopy (HE), 3. Transmission electron microscopy and 4. Immunohistochemistry for vascular endothelial growth factor (VEGF) and receptor 2 for VEGF (VEGFR-2). The activity of NADH in groups IV, V and VI (30±1,26; 33,47±2,15; 31,67±1,77 - intermediate fiber) increased significantly (p> 0.05) in oxidative metabolism in relation to other groups. The activity of SDH showed a slight increase, only the group V (32,2±1,61 intermediate fiber) increased significantly (p> 0.05), but the pattern of metabolic increase was very similar in both reactions. The ATPase activity showed no differences between groups nor in acid or alkaline. The qualitative analysis showed a pattern of increased expression of VEGF and VEGFR-2 directly proportional to the energy density of laser. Light microscopy showed rounded muscle fibers and peripheral flattened nuclei, which become more rounded with the highest energy densities. Ultrastructurally the irradiation with higher energy densities showed mitochondria of different sizes and shapes and dilated cisterns of sarcoplasmic reticulum between the myofibrils. It is concluded that higher densities of laser was able to increase the oxidative metabolism without altering the contractile capacity, increasing nuclei volume, modify ultrastructure of muscle fibers and the expressions of VEGF and VEGFR-2.
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Yin, Lu. "Rational Design and Development of Anti-Angiogenic Protein Agents". Digital Archive @ GSU, 2011. http://digitalarchive.gsu.edu/biology_diss/109.
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Inhibition of angiogenesis is an effective and low toxic therapeutic avenue for the treatment of cancer patients in addition to traditional interventions. Majority of current available angiogenesis inhibitors for cancer therapies are growth factor inhibitors and small molecule tyrosine kinase inhibitors. A number of endogenous proteins and/or proteolytic fragments of extracellular matrix proteins are shown to have the activity of inhibition of angiogenesis by directly targeting endothelial cells. Structural analyses have indicated that a common structure of anti-parallel β-sheet with a highly positively charged surface presents in many of those inhibitors. This common structural feature is critical for the maintenance of their anti-angiogenic function. With this structural information, we have designed and developed a new class of anti-angiogenic proteins by integrating the short anti-parallel β-sheet forming sequences of endogenous anti-angiogenic proteins into a stable host protein, the extracellular domain-1 of cluster of differentiation 2 molecule (CD2D1). 1D 1H NMR spectra analyses indicated that the designed anti-angiogenic protein (ref to as ProAgio) folded as a β-sheet structure similar to that of the parental protein, CD2D1. ProAgio inhibited the growth of human umbilical vein cells (HUVECs) without affecting the growth of epithelial cells, suggesting a specific effect to endothelial cells. ProAgio effectively reduced endothelial tubules formed by the co-culture of HUVECs and PC3 cells on matrix gel in vitro. The designed anti-angiogenic protein was further site-specifically PEGylated in order to improve PK/PD properties and reduce immunogenicity. Examinations with PC3 xenografts showed that both ProAgio and the PEGylated ProAgio dramatically inhibited tumor growth. Immunofluorescence staining analyses of the endothelial marker CD31 indicated dramatic decreases in tumor vessels in lengths and branching points. Histological and immunofluorescence staining analyses of tissue slices of major organs indicated that there were no pathological damages to the tissue structure or disruption of normal vessels associated with the treatment of our designed anti-angiogenic agent. Overall, our studies developed a novel anti-angiogenesis agent that may have great clinical potentials. Our concept of protein design can be extended to the development of other novel protein drugs.
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Cunningham, Crystal. "Expression of Chemokines and VEGFs in HNSCC". VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1787.
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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. The 5-year survival rate when the cancer remains as a primary tumor is 81% but when it metastasizes to distant sites, defined as a metastatic cancer, it decreases dramatically to 26%. Approaches to prevent these cancers from undergoing these metastatic changes can greatly improve the survival and outcome of these cancer victims. This current study is examining the expression profiles of chemokines and VEGFs in HNSCC. By investigation the underlying pathways involved in the expressions of chemokines and VEGFS we hope to sort out the transcriptional regulation of these molecules. We used pharmological inhibitors of several important kinase pathways and the receptors involved in the transcription of chemokines and VEGFs. This study specifically looked at the proangiogenetic chemokines, CXCL5 and CXCL8, and their receptor CXCR2, and their possible impact on VEGFs, specifically VEGF-C and VEGF-A. From experimentation we concluded that HNSCC uses the MAPK pathway for regulation of the chemokines CXCL5 and CXCL8, but not for its downregulation. VEGF-A showed to be positively controlled by the MAPK pathway. The Akt pathway was found to downregulate VEGF-C, possibly from CXCR2. VEGF-C was not under control of the chemokines’ expression, VEGF-C and VEGF-A were also differentially regulated. The current study has begun to sort out the expression and regulation of chemokines and VEGFs in HNSCC. There are still many unanswered questions about the role these molecules play in HNSCC, but hopefully these conclusions will aid in finding improved treatments for patients diagnosed with head and neck cancer.
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Barkefors, Irmeli. "Directing Angiogenesis : Cellular Responses to Gradients in vitro". Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-145525.
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Blood vessels are essential for the delivery of nutrients and oxygen to tissues, as well as for the removal of waste products. Patients with tumors, wounds or diabetes all have active angiogenesis, formation and remodeling of blood vessels, a process that is initiated and manipulated by gradients of secreted signaling proteins. This thesis describes the development of new microfluidic in vitro assays where directed migration of single endothelial cells and three dimensional vascular structures can be monitored in real time. Combining these assays with live imaging microscopy we have studied the behavior of endothelial cells in gradients of proangiogenic factors as well as directed sprouting in embryonic kidneys and stem cell cultures. With the 2D assay we have quantified endothelial cell chemotaxis towards FGF2, VEGFA165 and VEGFA121 and we also demonstrate that constant levels of VEGFA165, but not of FGF2, are able to reduce chemokinesis of endothelial cells. In the 3D migration chamber we have studied directed endothelial cell sprouting in mouse embryonic kidneys and embryoid bodies in response to VEGFA gradients. In both models directed angiogenesis is detected towards increasing levels of growth factor. Using the microarray technique on differentiating embryonic stem cells we have been able to identify the gene exoc3l2 as potentially involved in angiogenesis and endothelial cell migration and we present evidence that ExoC3l2 is associated with the exocyst complex; an important regulator of cell polarity. We have also shown that siRNA mediated gene silencing of exoc3l2 results in impaired VEGFR2 phosphorylation as well as loss of directionality in response to a VEGFA gradient.(Faculty of Medicine)
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Soueid, Jihane. "Contribution des facteurs de croissance vasculaire et de leurs récepteurs au développement du SNC : rôle du VEGFR-3 et de son ligand VEGF-C". Paris 6, 2010. http://www.theses.fr/2010PA066667.
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J'ai étudié la contribution de la signalisation du facteur de croissance endothéliale vasculaire C (VEGF-C) et son récepteur VEGFR-3 à la neurogénèse postnatale. J'ai d'abord généré une lignée transgénique murine BAC Vegfr3::YFP. Au niveau de la zone subventriculaire adulte, Vegfc s'exprime dans les cellules épendymaires et astrogliales. Vegfr3 est exprimé par la majorité des astrocytes, incluant les cellules souches neurales (CSN) caractérisées par la possession d'un cil primaire, l'expression de GFAP et un cycle de division cellulaire lent. In vitro, ces cellules isolées par FACs à partir de cerveaux de souris Vegfr3::YFP ont un potentiel souche d'autorenouvellement et de multipotence. In vivo, la surexpression du VEGF-C dans le télencephale adulte, stimule les cellules sous-ventriculaires VEGFR3 et promeut la neurogenèse sans effet angiogénique. La déletion du gène Vegfr3 et le bloquage de la signalisation VEGFR-3 avec des anticorps spécifiques réduisent la population astrogliale et inhibent la neurogenèse. Cette étude montre le rôle direct de VEGF-C/VEGFR-3 sur les astrocytes sous ventriculaires, les CSN et la neurogenèse. Par ailleurs, deux modèles murins sont en cours de production : Vegfr3 Cre-ERT2 exprimant la recombinase Cre inductible au tamoxifene qui permettra de tracer le lignage des cellules VEGFR-3 chez l'embryon et l'adulte. Vegfr3::channelRhodopsine2-GFP, exprimant la protéine photoactivable channel Rhodopsine-GFP, permettra la photoactivation des cellules VEGFR-3 afin d'analyser leur physiologie et leurs circuits de connexions. Enfin j'ai réalisé l'étude du patron d'expression de Vegfr3 et de Vegfc au cours du développement chez le poulet et la souris
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Eubank, Tim. "M-CSF and GM-CSF induce human monocytes to express either pro- or anti-angiogenic factors". The Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1069772001.
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Redondo, Alexandre Rodrigues. "Determinação do sítio de ligação de um peptídeo anti-angiogênico em seus receptores". Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/46/46131/tde-11042017-084254/.
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A angiogênese é um processo fundamental e fisiológico de organismos vertebrados, sendo responsável pela formação de novos vasos sanguíneos a partir dos já existentes. Entretanto, a angiogênese pode ocorrer também em condições patológicas, como causa ou consequência de doenças. Um exemplo disso está nos tumores, que para crescer além de alguns milímetros cúbicos, necessitam de um suprimento adequado de oxigênio e nutrientes, e, portanto, dependem da angiogênese. Por isso, compostos que inibem a angiogênese já estão em uso na clínica, não só para o tratamento de tumores, mas também de outras doenças dependentes da angiogênese, as retinopatias. Neste projeto, daremos continuidade à linha de pesquisa do nosso grupo, que procura identificar e validar peptídeos com potencial translacional (pré-fármacos), por apresentarem atividade anti-angiogênica. Utilizando a metodologia do Phage Display, nosso grupo identificou e caracterizou um hexapeptídeo, que foi selecionado por interagir com os receptores do principal fator iniciador da angiogênese, o VEGF (fator de crescimento endotelial vascular). Os receptores de VEGF (ou VEGFR) são proteínas do tipo receptor tirosina quinase, expressos em células endoteliais e essenciais para a iniciação e progressão da neovascularização. O hexapeptídeo identificado em nosso laboratório liga-se ao VEGFRs e inibe a formação de vasos sanguíneos in vivo em modelos animais de angiogênese. Neste trabalho, procuramos estender os estudos com este hexapeptídeo para identificar o sítio de ligação do mesmo no VEGFR e avançar em modelos que permitam a determinação dos requisitos estruturais de interação peptídeoreceptor. Com estes conhecimentos, poderemos num futuro próximo, caminhar para o desenvolvimento racional de moléculas peptideomiméticas com propriedades anti-angiogênicas.Angiogenesis is a fundamental and physiological process for vertebrate organisms, being responsible for the formation of new blood vessels, sprouting from the existent ones. However, angiogenesis may occur in pathological conditions, being cause or consequence of diseases. One example is tumor development. To grow beyond a few cubic millimeters, tumors need a suitable supply of oxygen and nutrients, and, therefore, they are dependent of angiogenesis. In fact, anti-angiogenic compounds are already in therapeutic use, targeting not only tumors but other angiogenesis dependent diseases, like retinopathies. In this project, we expand research from our own group to identify and develop anti-angiogenic peptides with translational potential (pre-drugs). Using Phage Display methodology, our group identified and characterized a hexapeptide, that was selected based on its capacity to interact with the receptors for the main initiator factor of angiogenesis, the VEGF (Vascular Endothelial Growth Factor). VEGF receptors (VEGFR) are tyrosine kinase proteins, expressed by endothelial cells and essential for neovascularization initiation and progress. The hexapeptide identified in our lab binds to VEGFRs and inhibit blood vessel formation in vivo when tested in an angiogenesis animal model. In this study, we seek to further understand the interaction of this hexapeptide with its receptor by identifying its binding domain on VEGFR and develop models that will allow the determination of the structural requirements for interaction of this receptor ligand pair. With this knowledge, we can in a near future progress to a rational development of novel peptidemimetic molecules with angiogenic properties similar to this hexapeptide.
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Sawamiphak, Suphansa. "EphrinB2 regulates VEGFR2 function in developmental and tumor angiogenesis". Diss., lmu, 2010. http://nbn-resolving.de/urn:nbn:de:bvb:19-118766.
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Testini, Chiara. "Regulation of VEGFR2 signaling in angiogenesis and vascular permeability". Doctoral thesis, Uppsala universitet, Institutionen för immunologi, genetik och patologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-300084.
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Angiogenesis and vascular permeability occur in physiological and pathological conditions. Angiogenesis denotes the process of blood vessel formation from preexisting quiescent vessels. Angiogenesis is initiated by proangiogenic factors, inducing endothelial cell sprouting, migration and anastomosis, followed by regression of the new vessels or maturation into a quiescent status. Vascular permeability is the process where blood vessels exchange nutrients, solutes and inflammatory cells with the surrounding tissue. Small molecules freely cross the endothelial wall, however macromolecules and cells leak out from the vasculature only after stimulation by certain factors, including VEGF. Angiogenesis and vascular permeability are tightly regulated physiological processes, but uncontrolled angiogenesis and excessive leakage lead to pathological conditions and the progression of several diseases. VEGF and its receptor VEGFR2 are critical players in angiogenesis and in vascular permeability. The binding of the ligand to the receptor is not the only event involved in the activation and regulation of the signaling cascade. Coreceptors, kinases, phosphatases, and other proteins involved in the trafficking of the complex modulate the signal amplitude and duration. VEGF/VEGFR2 complex combined with the coreceptor NRP1 has a strong pro-angiogenic action and a critical role in angiogenesis. Both VEGFR2 and NRP1 bind VEGF and can present VEGF in cis, when both VEGFR2 and NRP1 are expressed on the same endothelial cell or in trans, when NRP1 is expressed on an adjacent endothelial cell or another type of cell. Y949 and Y1212 are two of the main phosphorylation sites of VEGFR2 induced by VEGFA. The binding of phosphorylated Y949 to the SH2 domain of TSAd regulates vascular permeability leading to Src activation and adherens junction opening in vitro. Phospho-Y1212 is implicated in actin stress fiber remodeling via the adapter Nck, affecting the actin cytoskeleton and endothelial cell migration in vitro. Paladin is a vascular-enriched phosphatase-domain containing protein without reported phosphatase activity and is a negative regulator of insulin receptor and Toll-like receptor 9 signaling. In this thesis work, I have investigated the spatial dynamics of NRP1/VEGFR2 complex formation (in cis and in trans) for coordinating VEGF-mediated angiogenesis in physiological and in pathological conditions (Paper I). I have studied, in vivo, the role of VEGFR2 Y949 in vascular permeability and metastatic spread (Paper II) and the role of VEGFR2 Y1212 in angiogenic remodeling and vessel stability (Paper III). Furthermore, I have examined paladin’s role in regulating VEGF/VEGFR2 signaling and VE-cadherin junction stability, in angiogenic sprouting and vascular permeability (Paper IV). In conclusion, VEGF/VEGFR2 signaling is regulated by a multifactor system and each individual regulatory mechanism leads to a specific outcome in angiogenesis, vascular permeability and vessel stability.
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Pattarini, Lucia. "Post-translational modifications and molecular interactions regulating VEGFR2 activity". Doctoral thesis, Scuola Normale Superiore, 2009. http://hdl.handle.net/11384/85997.
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The work described in this thesis has been mainly focused on the study of
a key molecule involved in blood vessel formation, the tyrosine kinase
receptor VEGFR2.
Considering that VEGFR2 biology should be tighly regulated to allow proper
blood vessel formation and maintenance, we investigated two different
mechanims influencing VEGFR2 activity: post translational modification and
receptor complex formation.
Since VEGFR2 biology is governed through protein modication, mainly
phosphorylation, we decided to investigate the possible role of acetylation
in VEGFR2 activity. Combining biochemical and proteomic studies, we
showed that VEGFR2 is modified by acetylation. Starting from this
observation, we further investigated the impact of VEGFR2 acetylation on
protein stability and phosphorylation in response to ligand. These findings
are of particular interest, since, to our knowledge, this is the first report that
a tyrosine kinase receptor might be regulated by acetylation.
Additionally, we decided to elucidate the interaction of VEGFR2 with its
coreceptor Neuropilin1, with particular attention to the Neuropilin1
molecule, by taking advantage of the FRET imaging technique. Collectively,
our work characterizes VEGFR2-Neuropilin1 and Neuropilin1-Neuropilin1
complex formation in response to VEGFs and SEMA3A. Altough we do not
provide direct evidence for Neuropilin1 direct signalling, our data suggest
that Neuropilin1 oligomer formation might be a key step in Neuropilin1
biology.
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Edholm, Dan. "VEGFR-2 in Endothelial Differentiation and Vascular Organization". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Universitetsbiblioteket [distributör], 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8579.
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Arantes, Ricardo Vinicius Nunes. "Estudo da angiogênese e da expressão temporal do VEGF e dos seus receptores VEGFR-1/Flt-1 e VEGFR-2/Flk-1 durante o reparo ósseo alveolar normal e com uso terapêutico de um antiinflamatório não esteroidal seletivo para COX-2 em ratos". Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/25/25149/tde-12062012-151744/.
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Objetivo: Avaliar o efeito do Meloxicam sobre a expressão do VEGF e de seus receptores durante o reparo alveolar pós-exodontia em ratos. Material e Método: Foi realizada a exodontia do incisivo superior direito em 180 ratos Wistar, machos, com 60 dias de idade, subdivididos em dois grupos: 1) Grupo controle (n=90): os animais receberam injeção intraperitoneal de 0,1 ml de solução 0.9% NaCl diariamente, durante 7 dias; e 2) Grupo experimental (n=90): os animais receberam injeção diária de 3mg/kg de massa corporal de Meloxicam em solução 0.9%NaCl, durante 7 dias. Após 3, 7, 10, 14, 21 e 30 dias, os alvéolos foram coletados, fixados em formol a 10% em tampão fosfato, radiografados e processados histologicamente. Para o PCR-RT, as peças foram colocadas em Trizol® e armazenadas a -80ºC e para o Western blotting armazenado a -80ºC. Cortes histológicos semi-seriados (250m de intervalo entre os cortes) de todo o alvéolo no sentido transversal foram obtidos e corados pela hematoxilina e eosina. Avaliou-se nesses cortes pelo método morfométrico de volumetria de pontos a densidade de volume de tecido ósseo (%TO), tecido conjuntivo (%TC), coágulo sanguíneo (%Coa) e vaso sanguíneo (%VS). Os dados obtidos foram submetidos ao teste t para comparação entre os grupos por período e a ANOVA seguido do teste de Tukey para comparação entre períodos dentro de cada grupo, adotando nível de significância de p<0,05. Resultados: A análise radiográfica mostrou ocorrência com o transcorrer do tempo alterações no contorno da cortical óssea e redução no tamanho do alvéolo, além de um pequeno aumento na radiodensidade na região central do alvéolo. Morfologicamente, o grupo experimental exibiu em todos os períodos analisados, um atraso no processo de reparo em relação ao controle, exibindo maior quantidade de coágulo sanguíneo com lenta substituição por tecido conjuntivo e menor reabsorção da cortiça óssea alveolar e da formação/remodelação óssea. Na análise morfométrica a %TO no grupo controle foi de 0.817, 0.255, 0.368, 0.409 e 0.453 vezes maior em relação ao grupo experimental nos períodos de 3, 7, 10, 14 e 21 dias, respectivamente. Quanto a %Coa, os valores no grupo controle foram 0,097, 0,611, 1,189 e 1.497 vezes menor em relação ao grupo experimental nos períodos de 7, 10, 14 e 21 dias,respectivamente. A %VS no grupo controle apresentou 0,328 e 0,439 vezes maiores em relação ao grupo experimental nos períodos de 10 e 14 dias, respectivamente. A %TC não apresentou diferença estatística entre os grupos. As imunomarcações para VEGF e VEGFR-1 foram observadas em osteoblastos e osteócitos na cortical alveolar, e em fibroblastos no interior do alvéolo, com diferença estatisticamente significante apenas para VEGFR-1, onde a imunomarcação no grupo controle foi 0,544; 0,325 e 0,325 vezes maior em relação ao grupo experimental nos períodos de 3, 7 e 10 dias, respectivamente. As análises do PCR-RT para VEGF no grupo controle foi 1,274 vezes maior no período de 10 dias em relação ao grupo experimental. Na expressão de RNAm para VEGFR-1, o grupo controle foi 1,431; 0,951 e 0,845 vezes maior nos períodos de 3, 10 e 30 dias, respectivamente, em relação ao grupo experimental e VEGFR-2 no grupo controle de 4,649 e 0,790 vezes maior nos períodos de 3 e 7 dias, respectivamente. A expressão protéica do VEGF no grupo controle foi 0,365; 1,056; 2,187 e 0,350 vezes maior nos períodos de 3; 7; 10 e 14 dias em relação ao grupo experimental. Conclusões: Com base nos resultados obtidos foi possível concluir que o uso do antiinflamatório Meloxicam, administrado diariamente por 7 dias, altera a expressão do RNAm e das proteínas do VEGF e de seus receptores VEGFR, além de atrasar o processo de reparo e de remodelação óssea alveolar pós-exodontia.Objective: To evaluate the effect of Meloxicam on the expression of VEGF and its receptors during the post-extraction alveolar healing in rats. Material and Methods: The extraction of the right upper incisor was made in 180 male Wistar rats, aged 60 days old. The sample was divided in: 1) Control group (n=90) - the rats received intraperitoneal injection of 0.1 ml of 0.9% NaCl daily for 7 days, and 2) experimental group (n=90) - the rats received intraperitoneally 3mg/kg body weight of Meloxicam in 0.9% NaCl solution daily for 7 days. At 3, 7, 10, 14, 21 and 30 days later, the alveolar samples were collected, fixed in 10% formaldehyde in phosphate buffer, radiographed and histologically processed. For RT-PCR, the samples were placed in Trizol and stored at -80° and for Western blotting stored at -80°. Transversal semi-serial histological sections (with 250 um interval) of the whole alveolus were obtained and stained with hematoxylin and eosin. In these sections the volume density of bone tissue (% TO), connetive tissue (% CT), blood clot (Coa%) and blood vessel (% VS) was evaluated by point counting volumetry morphometric method. The obtained data were compared between groups for period by \"t\" test and between periods within each group by ANOVA and Tukey test, with a p<0.05 significance level. Results: a) The radiographic analysis showed changes in the contour of the cortical alveolar bone , reduction in size of the alveolus, and a small increase in radiodensity in their central region ; b) Morphologically the experimental group showed, in all periods, a delay in the repair process as compared to control, displaying greater amount of blood clot with slow replacement by connective tissue and lower cortical alveolar bone resorption and bone formation / remodeling c) In morphometric analysis the %TO in the control group were 0.817, 0.255, 0.368, 0.409 and 0.453 times higher than the experimental group during periods of 3, 7, 10, 14 and 21 days , respectively. The %Coa, the values in the control group were 0,097, 0,611, 1,189 and 1.497 times lower than in the experimental group on days 7, 10, 14 and 21 days respectively. The %VS in the control group showed 0.328 and 0.439 times higher than in the experimental group on days 10 and 14 days respectively. The% CT showed no statistical difference between groups. d) The imumunostaining for VEGF and VEGFR-1 were observed in osteoblasts and osteocytes in the cortical alveolar, and fibroblasts within the alveolus, which was statistically significant only for VEGFR-1, where the immunostaining in the control group was 0,544; 0,325 and 0,325 times higher than the experimental group during periods of 3, 7 and 10 days respectively e) The RT-PCR analysis for VEGF in the control group was 1.274 times higher within 10 days compared to the experimental group. In the expression of mRNA for VEGFR-1, the control group was 1,431; 0,951 and 0,845times higher in periods of 3, 10 and 30 days, respectively, compared to the experimental group and VEGFR-2 was 4.64 and 0.79 times higher in periods of 3 and 7 days, respectively, and f) The protein expression of VEGF in the control group was 0,365; 1,056; 2,187 and 0,350 times higher in periods of 3, 7, 10, 14 and 21 days compared to the experimental group. Conclusions: Based on the present results it was concluded that the use of Meloxicam, antiinflammatory administered daily for 7 days, alters the expression of mRNA and protein of VEGF and its receptors VEGFR, and slows the process of repair and remodeling post extraction alveolar
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Kappas, Nicholas Chris Bautch Victoria L. "Analysis of the VEGFr1 (Flt-1) isoforms in vascular development". Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2006. http://dc.lib.unc.edu/u?/etd,601.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2006.Title from electronic title page (viewed Oct. 10, 2007). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biology." Discipline: Biology; Department/School: Biology.
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Ulyatt, Clare Louise. "Endothelial vegfrl expression and trafficking under normoxic and hypoxic conditions". Thesis, University of Leeds, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534445.
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Mittar, Shweta. "Regulation of VEGFR1 localisation and trafficking in human endothelial cells". Thesis, University of Leeds, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.435797.
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Jones, Matthew Callum. "The role of AVB3 and VEGFR2 endocytic recycling in angiogenesis". Thesis, University of Leicester, 2008. http://hdl.handle.net/2381/29624.
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Placental growth factor (PIGF) binds to VEGFR1 and is known to play a role in pathological angiogenesis, but its mechanism of action remains unclear. Endothelial cell migration in response to angiogenic stimuli requires coordination of adhesive function with VEGFR signalling, and I have studied the intracellular trafficking of integrins and VEGFRs in primary cultured human umbilical vein endothelial cells (HUVECs). VEGFR2 and alphavbeta3 integrin cycled rapidly between the plasma membrane and EEA1/Rab4-positive early endosomes, whereas VEGFR1 remained at the plasma membrane and was not subject to rounds of endo- exocytosis. Treatment of HUVECs with PIGF or VEGF-A promoted the rapid and coordinate mobilisation of both VEGFR2 and alphavbeta3 from these endosomes to the plasma membrane, via a mechanism that was developed on inactivation of GSK-3beta but did not require the activity of PKD1, nor the tyrosine kinase activity of VEGFRs. Furthermore, RNAi of Rab4a and pharmacological inhibition of alphav integrin signalling opposed PIGF-promoted endothelial cell vessel branching and cross-bridge formation in an organotypic tube formation assay.;Taken together these data show that PIGF can influence endothelial cell function by controlling the endocytic recycling of alphavbeta3 integrin. This recycling pathway is required to induce vessel branching and the formation of a complex endothelial cell vessel network. In addition, regulation of VEGFR2 recycling by VEGFR1 represents a novel mechanism for mediating receptor cross talk during angiogenesis. Therefore, I have identified a novel pathway by which PIGF/VEGFR1 is able to positively influence the angiogenic response.
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Allen, Jennifer L. "Trafficking of VEGFR2 in angiogenesis : the role of myosin Vb". Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.685045.
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Angiogenesis is the formation of new blood vessels from existing vasculature. It is a process fundamental to normal development and tissue repair, and is implicated in many pathological conditions. The major pro-angiogenic factor is VEGF, for which the major receptor is VEGFR2. Blood vessels are lined with endothelial cells that express VEGFR2 to detect VEGF in surrounding tissue. This detection mediates cell responses to initiate fOlmation of angiogenic sprouts. VEGFR2 belongs to the family of receptor tyrosine kinases. Ligand binding to the extracellular domain results in receptor dimerisation and autophosphorylation of the intracellular kinase domain. This activates multiple downstream signalling cascades, which in the case of VEGFR2 have four main outcomes: proliferation, migration, permeability and survival. Receptor activation is often followed by internalisation and degradation to downregulate signalling pathways. VEGFR2 has unusual trafficking kinetics for a receptor tyrosine kinase because it constitutively internalises and recycles back to the cell surface in the absence of VEGF. It is distributed such that a significant proportion is localised to an intracellular endosomal storage pool. Moreover, the behaviour of VEGFR2 during angiogenesis depends on the location of the endothelial cell within the growing sprout. The importance of this unusual trafficking in relation to signal transduction is poorly understood. My aim was to elucidate how VEGFR2 trafficking controls angiogenic signalling. I worked to identify sorting proteins required for VEGFR2 trafficking. I investigated proteins that are known to mediate the trafficking of other cargoes. Using an ELISA-based screen, I discovered several potential regulators of VEGFR2, including the motor protein myosin Vb. Myosin Vb traffics organelles along actin filaments and has been described in the recycling of many receptors. I used biochemical methods to establish an essential role for myosin Vb in VEGFR2 recycling in unstimulated conditions. I show that myosin Vb depletion impairs vessel formation in an organotypic angiogenesis assay and disrupts phosphorylation of several kinases activated upon VEGF stimulation in endothelial cells. Furthermore, I show that myosin Vb is required for the polarised distribution of VEGFR2 in endothelial cells to enable chemotactic migration towards VEGF. My data suggest that myosin Vb-dependent constitutive trafficking of inactive VEGFR2 is necessary for angiogenesis.
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Iljin, Kristiina. "Transcriptional regulation of endothelial cell-specific Tie1 and Vegfr3 genes". Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/laa/haart/vk/iljin/.
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Boujut, Margot. "Ligands Photo-Actifs pour l'imagerie de fluorescence du VEGFr". Thesis, Normandie, 2020. http://www.theses.fr/2020NORMR063.
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Les VEGFr (Vascular Endothelium Growth Factor receptors, récepteurs des facteurs de croissance de l’endothélium vasculaire) sont des protéines responsables de l’angiogenèse, c’està-dire, la croissance des vaisseaux sanguins. De fait, ils sont impliqués dans les maladies liées à une vascularisation néfaste comme dans la croissance des tumeurs cancéreuses ou de néovascularisation rétinienne. Traiter ces vaisseaux sanguins sans atteindre les tissus sains est un enjeu qui nécessite de les imager spécifiquement et précisément, ces deux critères pouvant être atteints par imagerie de fluorescence. La spécificité en imagerie de fluorescence repose sur l’emploi d’une sonde, c’est-à-dire un fluorophore sélectif du phénomène à imager. Pour synthétiser des sondes sélectives, nous nous sommes inspirés d’un ligand connu du VEGFr : l’axitinib. La structure chimique de l’axitinib comporte un hétérocycle indazole avec deux rôles essentiels : (i) dans la fluorescence de l’axitinib, (ii) dans sa sélectivité pour le VEGFr. Cette structure a été modifiée de façon à introduire des substituants rendant la molécule plus fluorescente tout en conservant au mieux le squelette responsable de l’activité biologique. Une librairie d’une vingtaine de fluorophores a été synthétisée et étudiée pour des applications en imagerie de fluorescenceVEGFr (Vascular Endothelium Growth Factor receptors) are proteins responsible for the angiogenesis, meaning the growth of blood vessels. Consequently, they are involved in diseases due to harmful vascularization such as tumor growth or retinal neovascularization. Treating those blood vessels without harming healthy tissues is an issue. It requires specific and precise images of the blood vessels, both criteria being achievable thanks to fluorescent imaging. The specificity of fluorescent imaging relies on the use of a probe, meaning a selective fluorophore. To synthetize selective probes, we were inspired by a known ligand of the VEGFr: the axitinib. The chemical structure of the axitinib has an indazole heterocycle with two key roles: (i) in the fluorescence of the axitinib, (ii) in its selectivity for the VEGFr. Substituents were introduced to increase the overall fluorescence of the molecule while preserving the backbone responsible for the biological activity to the best of our ability. A library of about twenty fluorophores was synthetized and studied for applications in fluorescent imaging
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Nilsson, Ingrid. "Hypoxia, PDGF and VEGF in Vascular Development". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6894.
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Carbary, Jordan Leslie. "Quantum Dots Targeted to VEGFR2 for Molecular Imaging of Colorectal Cancer". Diss., The University of Arizona, 2015. http://hdl.handle.net/10150/565917.
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Advances in optical imaging have provided methods for visualizing molecular expression in tumors in vivo, allowing the opportunity to study the complexity of the tumor microenvironment. The development of fluorescent contrast agents targeted to molecules expressed in cancer cells is critical for in vivo imaging of the tumors. Contrast agents emitting in the near infrared (NIR) allow for an increased depth of penetration in tissue due to decreased absorption and scattering. There is also significantly less autofluorescence from tissue in the NIR. Quantum dots are nanoscopic particles of semiconductors whose fluorescent emission wavelength is tunable by the size of the particle with desirable fluorescent qualities such as a wide range of excitation wavelengths, a narrow emission band, high quantum efficiency, high photostablility, and they can be produced to emit throughout the NIR imaging window. It has been shown that vascular endothelial growth factor receptor 2 (VEGFR2) is upregulated in many cancers, including colorectal, as it is important in tumor angiogenesis and is considered a predictor for clinical outcome and, in some instances, is used for targeted therapy with anti-angiogenic drugs. For these reasons, quantum dots bioconjugated to VEGFR2 antibodies have the potential to provide contrast between normal tissue and cancer, as well as a mechanism for evaluating the molecular changes associated with cancer in vivo. In this dissertation, we present on the design of two contrast agents using quantum dots targeted to VEGFR2 for use in the molecular imaging of colon cancer, both ex vivo and in vivo. First, as a preliminary ex vivo investigation into their efficacy, Qdot655® (655nm emission) were bioconjugated to anti-VEGFR2 antibodies through streptavidin/biotin linking. The resulting QD655-VEGFR2 contrast agent was used to label colon adenoma in vivo and imaged ex vivo with significant increase in contrast between diseased and undiseased tissue, allowing for fluorescence based visualization of the VEGFR2 expressing diseased areas of the colon with high sensitivity and specificity. Then, QD655-VEGFR2 was used in a longitudinal in vivo study to investigate ability to correlate fluorescence signal to tumor development over time using optical coherence tomography and laser induced fluorescence spectroscopy (OCT/LIF) dual-modality imaging. The contrast agent was able to target VGEFR2 expressing diseased areas of colon; however, challenges in fully flushing the unbound contrast agent from the colon before imaging arise when moving from ex vivo imaging to in vivo image. Lastly, lead sulfide (PbS) quantum dots were made by colloidal synthesis to emit at a 940 nm (QD940) and conjugated to anti-VEGFR2 primary antibodies through streptavidin/biotin linking. The resulting QD940-VEGFR2 contrast agent was then used to label cells in vitro. The QD940-VEGFR2 molecules were able to positively label VEGFR2 expressing cells and did not label VEGFR2 negative cells. Very low photoluminescence and large amounts of aggregation after conjugation of the quantum dot to streptavidin was detected. Improvements to the quantum dot stability through synthesis, capping and conjugation techniques must be made for this contrast agent to be effective as a contrast agent for cancer imaging.
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Inamdar, Shivangi Makarand. "Dab2 plays a role in the post-endocytic trafficking of VEGFR2". Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/2225.
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Angiogenesis is a crucial process under both physiological and pathological conditions. Vascular endothelial growth factor (VEGF) A and its cognate receptor, vascular endothelial growth factor receptor 2 (VEGFR2) are key regulators of angiogenesis. Plasma membrane (PM) levels of VEGFR2 are regulated by de novo synthesis, and by both exocytic and endocytic trafficking. VEGF-binding to VEGFR2 induces phosphorylation of key tyrosine residues located in the cytosolic domain of the receptor, followed by clathrin-mediated endocytosis and signal transduction leading to vascular morphogenesis. Disabled protein 2 (Dab2) is a cytosolic, clathrin-adaptor protein that is known to regulate endocytosis of certain cell surface receptors. Studies of Dab2 function have revealed its role in the development of embryonic vasculature. However, the mechanism of Dab2 function, particularly in conjunction with endosomal VEGFR2, remains poorly understood. Our results show that Dab2 interacts with VEGFR2 and that upon VEGF stimulation the two proteins co-localize within Rab5-positive early endosomes. Knockdown of Dab2 reduces levels of VEGF-induced phosphorylation of VEGFR2 at residue Y1175. This is significant because phosphorylation of VEGFR2-Y1175 is crucial for pro-angiogenic signal transduction. Moreover, knockdown of Dab2 causes an increased trafficking of VEGFR2 to late endosomes (LE). Finally, this altered VEGFR2 trafficking following Dab2 knockdown has major functional consequences for endothelial cells, as they are unable to undergo morphogenesis into tube-like structures in an in vitro assay of angiogenesis. Collectively, our data show that Dab2 plays a crucial role in VEGFR2 trafficking in the endocytic system and this impacts receptor signaling and endothelial cell morphogenesis during angiogenesis.
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Hines, Danita Martha. "VEGETARIANS AND VEGANS IN KENTUCKY". UKnowledge, 2010. http://uknowledge.uky.edu/gradschool_theses/49.
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Kentucky has a health crisis and most of the causes can be linked to diet, smoking and physical activity. Vegetarian and vegan diets have numerous benefits for many diet related health problems such as obesity, heart disease, Type 2 diabetes and certain cancers. There has been limited research on vegetarians and vegans in the United States and none in Kentucky. This study used an anonymous electronic survey to examine the different characteristics, behaviors, experiences and opinions of adult vegetarians and vegans in Kentucky. Results were compared to statistical data reported on the general population of Kentucky. Calculated body mass index (BMI) from self-reported height and weight showed 36% of vegetarians and 21% of vegans to be overweight or obese compared to 67% of the general Kentucky population being overweight or obese. The impact on BMI due to type of plant based diet (vegetarian or vegan) was found to be of greater significance (p=0.0030) than that of exercise. Reports from both groups indicated that they may be underserved by health care professionals. These findings have important implications for dietitians, dietetics education programs and health care providers concerned with high rates of obesity and chronic diseases.
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Sattler, Florentine [Verfasser], Sabine [Akademischer Betreuer] Mihm, Jochen [Akademischer Betreuer] Gaedcke y Martin [Akademischer Betreuer] Oppermann. "Zytokinabhängige Expression von EGF und VEGF und ihrer Rezeptoren EGFR und VEGFR-1 im Tumormikromilieu des kolorektalen Karzinoms / Florentine Sattler. Gutachter: Jochen Gaedcke ; Martin Oppermann. Betreuer: Sabine Mihm". Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2014. http://d-nb.info/1054191530/34.
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Capp, Clarissa. "Expressão do fator de crescimento endotelial vascular (VEGF) e de seus receptores (VEGFR 1 e 2) em amostras de tecido tireoidiano de pacientes com carcinoma medular de tireóide". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2009. http://hdl.handle.net/10183/17771.
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Jia, Tao. "Définition de molécules théranostiques bifonctionnelles pour le traitement du cancer". Thesis, Université Grenoble Alpes (ComUE), 2016. http://www.theses.fr/2016GREAV086/document.
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L’angiogenèse tumorale réfère à la capacité d’une tumeur à stimuler la formation de nouveaux vaisseaux sanguins. L’induction de l’angiogenèse dépend notamment de la présence de certains récepteurs exprimés à la surface de cellules endothéliales et tumorales. Ces récepteurs sont impliqués dans la formation de nouveaux vaisseaux sanguins mais aussi dans la progression des tumeurs, l’invasion locale des tissus avoisinants et la formation de métastases. Nous nous intéressons ici essentiellement aux récepteurs de type intégrines (et surtout l’intégrine αvß3) ou neuropiline-1 (NRP1).Les intégrines sont des récepteurs transmembranaires décrits initialement parce qu’ils permettent aux cellules d’adhérer et de se déplacer sur la matrice extracellulaire (ECM) en particulier parce qu’elles se lient à la séquence tri-peptidique RGD, mais elles interviennent aussi directement et indirectement dans les échanges biochimiques entre les cellules et leur micro-environnement. NRP1 est un corécepteur du VEGF (vascular endothelial growth factor). Pour cela, NRP1 s’associe au récepteur principal VEGFR2, surexprimé dans les tumeurs et dont l’expression a été corrélée avec l’angiogenèse. Il est très important de noter que l’intégrine αvß3 et le récepteur NRP1 peuvent interagir physiquement et fonctionnellement. Notre hypothèse de travail est alors qu’en bloquant la fonction de ces 2 récepteurs nous pourrons augmenter l’efficacité des thérapies anti-angiogèniques anti-tumorales.Nous avons généré des nanoparticules de silices bifonctionnelles car elles présentent à leur surface à la fois des peptides cycliques cRGD ciblant l’intégrine αvß3 et ATWLPPR qui cible NRP1. Nous avons testé des ratio différents de peptides cRGD et ATWLPPR (100/0, 25/75, 50,75/50/25 et 0/100), et nous avons aussi optimisé le nombre total de ces ligands/NP. Nous avons analysé l’affinité des différentes molécules, leur sélectivité et activité biologique ainsi que leurs propriétés anti-angiogéniques et anti-tumorale en particulier sur des cellules endothéliales humaines (ECs) et sur des lignées de cellules tumorales.Notre étude suggère que ces nanoparticules bifonctionnelles présentent un grand potentiel si leur composition est soigneusement définie. En particulier, elles peuvent présenter des activités extrêmement variables voir opposées suivant la nature et composition de leur surface et de la concentration à laquelle les NPs sont utilisées. En effet, à « haute concentration » en NP, ce qui correspond en fait à une faible concentration en peptides, nous montrons qu’il est possible d’obtenir un effet « pro-angiogénique » lié au recrutement d’autres récepteurs de facteurs de croissance (IGF1-R/IR) qui a priori ne devaient pas intervenir dans notre système, mais semblent pouvoir être fonctionnellement liés aux intégrines et/ou NRP1 en réponse aux particules présentant les 2 peptides cRGD et ATWLPPR. Ces résultats contribuent à expliquer certains échecs thérapeutiques des agents anti-angiogéniques mais nous permettent aussi de proposer des solutions attractives pour la définitions nouveaux agents thérapeutiquesTumor angiogenesis refers to the ability of a tumor to stimulate new blood vessels formation. Angiogenesis strongly depends on cell surface receptors and integrin activation to promote tumor progression, local invasion and dissemination. Integrins (especially integrin αvß3) and Neuropilin-1 (NRP1), a co-receptor of VEGFR2, are over-expressed in the tumor vasculature and by tumor cells, and their expression has been correlated with tumor progression. Importantly, integrin αvß3 and NRP1 can physically and functionally interact.The use of dual targeted drugs that block the integrin αvß3 and the NRP1 receptor simultaneously is thus expected to augment the anti-angiogenic and anti-tumor activities, as compared to each “mono-therapy” separately. During my PhD studies, in collaboration with the group of chemists leaded by Pr G. Subra, we generated different batches of bifunctional cRGD/ATWLPPR peptides coated nanoparticles (NPs) targeting integrin αvß3 and NRP1 simultaneously. We introduced different ratio of cRGD and ATWLPPR peptides (100/0, 25/75, 50/50, 75/25 and 0/100), and we also increased the amount of total ligands on the surface of the silica NPs. Systematic studies including molecules' affinity, selectivity, and biological activity as well as anti-angiogenic and anti-tumoral effects were performed on primary endothelial cells (ECs), immortalized ECs and several tumor cells. NPs properties were also evaluated in vivo in a mouse tumor model. We report here that these NPs present highly variable biological activities in ECs and tumor cells depending on the peptides ratio, surface coating of the NPs and on their concentration. In particular, “elevated” concentrations of NPs, which actually correspond to usual concentrations of peptides, can activate an unexpected IGF1-R/IR-AKT signaling pathway that could lead to a counter-productive pro-angiogenic activity (agonist instead of antagonist). This could mimic the conflicting results obtained in clinical trials using Cilengitide, an RGD-presenting peptide, and thus provide new areas of investigations and new possibilities to design active nano-drugs.This work can thus participate to the general effort of our research community to design efficient targeted anti-angiogenic therapies that could be applied in particular for cancer treatment
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Groot, Marcel. "Die Rolle des Tyrosinkinase-Rezeptors VEGFR-2 im neuronalen Kontext". Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2006. http://nbn-resolving.de/urn:nbn:de:swb:14-1166623362738-03904.
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Im Rahmen dieser Arbeit wurde die Rolle des Rezeptors VEGFR-2, Flk-1, im neuronalen Kontext untersucht. In einem ersten Schritt wurde in embryonalen Stammzellen der Maus das fluoreszierende Protein eGFP unter der Kontrolle regulatorischer Sequenzen des flk-1-Promotors, -Enhancers exprimiert. Nach der Differenzierung zu Sphäroiden wurden Endothelzellen nachgewiesen, die sowohl eGFP als auch das zelltypspezifische Oberflächenantigen CD31 ausprägen. Ebenso wurden nach der neuronalen Differenzierung in Gegenwart von Stromazellen eGFP-exprimierende Zellen identifiziert. Diese standen mit Zellen, die das für neuronale Vorläuferzellen charakteristische Protein Nestin ausprägten, in einem räumlichen Zusammenhang. Die Vorgehensweise, die Inaktivierung des flk-1-Gens mit der Differenzierung embryonaler Stammzellen in vitro zu kombinieren, sollte hier die Interpretation des Phänotyps des flk-1-defizienten Mausmodells ermöglichen. Der Rezeptor war während der neuronalen Differenzierung der Stammzellen auf Stromazellen in vitro für die Regulation der Anzahl der Vorläuferzellen essentiell. Ferner spielte der Rezeptor im Rahmen eines weiteren Differenzierungsmodells, das auf der Zugabe relevanter Wachstumsfaktoren beruht, eine instruktive Rolle im Hinblick auf die Identität der Neuronen. Kriterium war hier die differentielle Expression Homeobox-enthaltender Transkriptionsfaktoren. In einem zweiten Schritt wurden mit Hilfe dieses Modells differentiell-exprimierte Gene von Stammzellen des Wildtyps sowie Zellen mit einer Inaktivierung des flk-1-Gens nach der neuronalen Differenzierung durch subtraktive Hybridisierung in Verbindung mit der PCR identifiziert. Tatsächlich wurde das Protein PEA-15 nicht nur differentiell exprimiert sondern auch als Bestandteil des VEGFR-2-vermittelten Signalwegs identifiziert. Die biologischen Funktionen des Proteins PEA-15 wurden durch VEGF-vermittelte Phosphorylierung reguliert. Die Stimulation durch VEGF führte zunächst zu einer Aktivierung des Proteinkinase B-, Akt-Signalwegs. Für die Stimulation des Akt-Signalwegs war die Phosphorylierung der intrazellulären Tyrosinreste Y1052 und Y1057 des Rezeptors essentiell. Damit einhergehend wurde PEA-15 gegenüber der proteasomalen Degradation stabilisiert. Es wurde gezeigt, daß das Protein PEA-15 die Teilungsaktivität von Zellen beeinflusst. Die VEGF- vermittelte Stimulation führte zur Phosphorylierung der Mitogen-aktivierten Proteinkinasen ERK1 und ERK2. Die weitere Phosphorylierung der Substrate dieser Kinasen im Zellkern wurde durch Interaktion mit PEA-15 unterdrückt. Die Regulation des c-fos-Promotors war zugleich Indikator der Inhibition der Phosphorylierung betreffender Substrate sowie der proliferativen Aktivität. Auf diese Weise ist die Phosphorylierung von PEA-15 nach Stimulation durch VEGF für die Selektivität des Flk-1-vermittelten Signalwegs von unmittelbarer Bedeutung. Die Regulation der biologischen Funktion von PEA-15 erklärt die differentielle Ausprägung im Rahmen der neuronalen Differenzierung embryonaler Stammzellen in vitro. So war die Anzahl GFAP- beziehungsweise PEA-15-exprimierender Zellen nach Differenzierung muriner Stammzellen mit einer Inaktivierung des flk-1-Gens deutlich geringer. Die differentielle Expression identifizierter Gene wurde im Mausmodell nach konditionaler Inaktivierung des flk-1-Gens überprüft. Tatsächlich wurde Vimentin in verschiedenen Arealen des Gehirns differentiell ausgeprägt. Ein Zusammenhang zwischen der differentiellen Expression des Proteins PEA-15, der Anzahl GFAP-exprimierender Zellen und der Ausprägung des Rezeptors Flk-1 ergab sich aus der Identifikation einer Zellpopulation in der subgranulären Zone des Gyrus Dentatus. Dort wurde in flk-1-defizienten, adulten Mäusen eine geringere Anzahl GFAP-exprimierender Zellen nachgewiesen. Schließlich wurden sowohl im Cerebellum als auch im Cortex histologische Unterschiede deutlich, die sich im adulten Organismus aus der Inaktivierung des Rezeptors Flk-1 ergeben. Die vorliegende Arbeit zeigt, daß der Rezeptor VEGFR-2, Flk-1, im neuronalen Kontext eine Rolle spielt, die sich nicht ausschließlich auf die Vermittlung eines Schutzmechanismus gegenüber der neuronalen Apoptose beschränkt, sondern auch auf eine Beteiligung an der Neurogenese hinweist. Die Vorgehensweise, mit Hilfe der subtraktiven Hybridisierung Bestandteile Rezeptor-vermittelter Signalwege vor dem Hintergrund der Differenzierung embryonaler Stammzellen zu identifizieren, verdeutlicht die Eignung der Methode auch bei komplexen Zellpopulationen.
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Vojtickova, Margareta. "Development of VEGFR-2 inhibitors by ynamide- based click chemistry". Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAF050.
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Malgré d’intenses recherches, le cancer reste une des causes principales de mortalité dans le monde. Le développement de nouveaux produits actifs pour le traitement des cancers est de plus en plus nécessaire. Nous avons décidé de préparer de nouveaux composés anti-angiogéniques dérivés du composé III.1 (ligand du complexe PDB : 1Y6A) dores et déjà testé cliniquement. Cinq d’entres eux ont pu être synthétisés en utilisant une réaction Click entre un ynamide et un azide. La réaction Click catalysée au cuivre a permis de préparer cinq de nos 1,2,3-triazole cibles avec une excellente régiosélectivité. Bien que l’activité de ces composés soit bien moins importante que celle du composé oxazolique III.1 dont elles sont dérivées, nous avons montré qu’ils sont des ligands spécifiques de VEGFR-2 kinase et qu’elles représentent une nouveauté structurale intéressante dans l’espace très protégé des inhibiteurs de tyrosine kinasesDespite to the intensively research, cancer is still a leading cause of death worldwide. There are still developed new active compounds for cancer treatment. We have decided to prepare new antiangiogenic drugs based on already clinically tested III.1 from PDB complex 1Y6A. The in Silico-designed 1,2,3-triazole analogues of III.1 were prepared using a Click chemistry approach. In order to accomplish Click reactions two key building blocks: ynamides and azides were mandatory to synthetize. Copper catalyzed Click reactions were performed in very mild condition with quantitative regioselectivity. Five predicted triazolic compounds were prepared and sent for VEGFR-2 biologicall assays. Although the activities of triazolic compounds are significantly lower than the activities of their oxazolic isosters these compounds deliver structural novelty to IP crowded space of tyrosine kinase inhibitors
Napriek intenzívnemu výskumu, rakovina stále patrí k najčastejším príčinám úmrtia na svete. Neustále sú vyvíjané nové aktívne látky na liečbu rakoviny. Rozhodli sme sa pripraviť nové antiangiogenetické liečivá na základe klinicky testovaného III.1 z PDB komplexu 1Y6A. In Silico navrhnuté 1,2,3-triazolové III.1 analógy boli pripravené prostredníctvom Click chémie. Za účelom uskutočnenia Click reakcie, bolo nevyhnutné pripraviť dva kľúčové stavebné jednotky: ínamidy a azidy. Meďou katalyzované Click reakcie boli uskutočnené vo veľmi jemných podmienkach s kvantitatívnou regioselektivitou. Bolo pripravených päť nových triazolových látok, ktoré boli zaslané na VEGFR-2 biologické testy. Aj keď sú aktivity triazolových derivátov výrazne nižšie ako aktivity oxazolvých izostérov, tak tieto zlúčeniny vnášajú do oblasti tyrozín kinázových inhibítorov, ktorá obsahuje už rôznorodé látky, štruktúrnu originalitu