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1
Penco-Campillo, Manon. "Le VEGFC et les récepteurs CXCR1/2 : des cibles pertinentes pour le traitement des médulloblastomes pédiatriques." Electronic Thesis or Diss., Université Côte d'Azur, 2022. http://www.theses.fr/2022COAZ6025.
Texte intégralRésumé :
Le médulloblastome (MB) est la tumeur pédiatrique cérébrale la plus fréquente et la plus agressive. Malgré un traitement multimodal agressif, entraînant des effets secondaires importants, 30% des patients développent une résistance et rechutent suite à l'apparition de métastases dans les 5 ans. Les récidives ne peuvent être contrôlées par des traitements conventionnels (radio et chimiothérapie) ou ciblés (anti-angiogénique, anti-inflammatoire, anti-point de contrôle immunitaire). L'objectif de ma thèse est donc de découvrir de nouvelles cibles et stratégies thérapeutiques pertinentes pour ces patients au diagnostic ou après une rechute.Les MB sont des tumeurs très vascularisées. Le phénomène de résistance est, en partie, lié au développement de vaisseaux sanguins (angiogenèse) et lymphatiques (lymphangiogenèse) dans la tumeur, qui constituent les principales voies de dissémination métastatique. Le facteur de croissance des vaisseaux lymphatiques, le VEGFC, et ses récepteurs/co-récepteurs sont les acteurs majeurs de la lymphangiogenèse. Dans la première partie de ma thèse, j'ai montré que le VEGFC est inversement corrélé à la croissance et l'agressivité cellulaire du MB. En effet, le VEGFC diminue de manière autocrine la prolifération et la migration des cellules MB, ainsi que leur capacité à former des pseudo-vaisseaux in vitro. Les cellules résistantes à la radiothérapie présentent des niveaux élevés de VEGFC et perdent leur capacité à migrer et à former des pseudo-vaisseaux. L'irradiation réduit l'agressivité des cellules de MB par un processus dépendant du VEGFC. Les cellules surexprimant le VEGFC et les cellules résistantes à l'irradiation forment des tumeurs expérimentales plus petites chez la souris Nude. Le VEGC semble être un régulateur négatif de la croissance des MB. Ces résultats ouvrent la voie au développement de thérapies pro-VEGFC dans ces cancers.Dans la seconde partie de ma thèse, j'ai corrélé l'expression de la voie de signalisation pro-angiogénique et pro-inflammatoire ELR+CXCL/CXCR1-2 à une survie plus courte chez des patients atteints de MB. J'ai montré qu'un nouvel inhibiteur pharmacologique (C29) des récepteurs CXCR1-2 inhibe la prolifération, la migration dépendante de CXCL8/CXCR1/2, l'invasion et la formation de pseudo-vaisseaux par des cellules de MB sensibles ou résistantes à la radiothérapie. C29 réduit la croissance de MB expérimentaux dans un modèle de souris organotypique ex vivo et traverse la barrière hémato-encéphalique. Ainsi, le ciblage de CXCR1-2 représente une stratégie prometteuse pour le traitement des MB pédiatriques, en première ligne ou à la suite de rechutes.Mots-clés : médulloblastome pédiatrique, VEGFC/VEGFR, CXCR1-2, cytokines ELR+CXCL, thérapie ciblée, lymphangiogenèse, angiogenèse<br>Medulloblastoma (MB) is the most common and aggressive pediatric brain tumor. Despite aggressive multimodal treatment, resulting in significant side effects, 30% of patients develop resistance and relapse following the appearance of metastases within 5 years. Recurrences cannot be controlled by conventional (radio- and chemotherapy) or targeted (anti-angiogenic, anti-inflammatory, anti-immune checkpoint) treatments. The objective of my thesis is therefore to discover new targets and relevant therapeutic strategies for these patients at diagnosis or after a relapse.MBs are highly vascularized tumors. The phenomenon of resistance is, in part, linked to the development of blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels in the tumor, which constitute the main routes of metastatic dissemination. The lymphatic growth factor, VEGFC, and its receptors/co-receptors are the major players in lymphangiogenesis. In the first part of my thesis, I showed that VEGFC is inversely correlated to MB cell growth and aggressiveness. Indeed, VEGFC decreases the proliferation and migration of MB cells, as well as their ability to form pseudo-vessels in vitro, by an autocrine signalization. Cells resistant to radiotherapy show elevated levels of VEGFC and lose their ability to migrate and form pseudo-vessels. Irradiation reduces the aggressiveness of MB cells by a VEGFC-dependent process. VEGFC-overexpressing cells and radiation-resistant cells form smaller experimental tumors in nude mice. Thus, VEGC appears to be a negative regulator of MB growth. These results pave the way for the development of pro-VEGFC therapies in these cancers.In the second part of my thesis, I correlated the expression of the ELR+CXCL/CXCR1-2 pro-angiogenic and pro-inflammatory signaling pathway to shorter survival in patients with MB. I showed that a novel pharmacological inhibitor (C29) of CXCR1-2 receptors inhibits proliferation, CXCL8/CXCR1-2-dependent migration, invasion and pseudo-vessel formation by susceptible or resistant MB cells to radiotherapy. C29 reduces the growth of experimental MBs in an ex vivo organotypic mouse model and crosses the blood-brain barrier. Thus, targeting CXCR1-2 represents a promising strategy for the treatment of pediatric MB, at first line or at relapse.Key words: pediatric medulloblastoma, VEGFC/VEGFR, CXCR1-2, ELR+CXCL cytokines, targeted therapy, lymphangiogenesis, angiogenesis
2
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.
Texte intégralRésumé :
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.
3
Ferrão, Juliana Shimara Pires. "Tratamento com VEGFC para revascularização linfática em membros pélvicos de camundongos." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/10/10132/tde-08012014-112630/.
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A revascularização linfática é um desafio e o estabelecimento de novas estratégias terapêuticas podem melhorar a qualidade de vida de pessoas que sofrem de distúrbios linfáticos. O objetivo deste estudo foi verificar a capacidade de tratamento com VEGFC exógeno na melhoria da vascularização linfática de uma maneira dependente do tempo em membros pélvicos (MP) de camundongos após a remoção do linfonodo inguinal. O linfonodo inguinal esquerdo foi removido cirurgicamente para mimetizar patologias com diminuição da vascularização linfática. Densidade vascular linfática (Vv) e de comprimento (Lv) foram avaliadas por imunohistoquímica, seguidas de estereologia, após a cirurgia com ou sem o tratamento com VEGFC exógeno. O grupo controle não foi manipulado, mas recebeu soro fisiológico em vez de tratamento com VEGFC exógeno. As expressões do VEGFC e FLT4 local foram avaliadas por qPCR. Houve efeito do tempo sobre Vv e Lv no Grupo Cirurgia e diferença significativa entre os grupos Controle e Cirurgia nas três regiões estudadas (região proximal, média e distal) do MP esquerdo (MPE). A Lv mostrou diferença significativa entre os grupos Controle e Cirurgia somente na região média do MPE. A Vv e a Lv para o Grupo Tratamento foram maiores do que os outros grupos em todas as regiões do MPE. A expressão gênica do VEGFC e do FLT4 apresentou efeito do tempo em todas as regiões do MPE para os grupos Cirurgia e Tratamento. Ambas as expressões gênicas do VEGFC e do FLT4 apresentaram diferença significativa entre os grupos Controle e Cirurgia, entre os grupos Cirurgia e Tratamento e entre os grupos Controle e Tratamento. Os resultados mostraram que os camundongos são bons modelos experimentais para o uso de VEGFC exógeno como terapia de revascularização linfática, e o tratamento com VEGFC exógeno aumenta vascularização linfática já após 3 dias de dano linfático.<br>Lymphatic revascularization is a challenge and the establishment of new therapeutic strategies may improve quality of life from those suffering from lymphatic disorders. The objective of this study was to verify the VEGFC treatment capacity in improving lymphatic vascularization in a time-dependent manner in mouse hind limb (HL) after removal of inguinal lymphnode. The left inguinal lymphnode was surgically removed to mimetize pathologies with decreased lymphatic vascularization. Lymphatic vascular density (Vv) and length (Lv) were evaluated by immunohistochemistry followed by stereology after surgery and/or VEGFC treatment. Control group was not manipulated but received saline instead of VEGFC treatment. VEGFC and FLT4 local expression were assessed by qPCR. There was effect of time over Vv and Lv in the SG and significant difference between CG and SG in the three studied regions (proximal, medium and distal region) of the left HL (LHL). The Lv showed significant difference between CG and SG only in the medium region. The Vv and the Lv for TG were higher than the other groups in all regions of LHL. VEGFC and FLT4 gene expression presented time effect in all regions of the LHL for SG and TG. Both VEGFC and FLT4 gene expression presented significant difference between CG and SG, between SG and TG, and between CG and TG. The results show that mice are good experimental models for VEGFC use as therapy for lymphatic revascularization, and VEGFC treatment increased the lymphatic vasculature already after 3 days of lymphatic damage.
4
Dellinger, Mike. "Contrasting Defects in Lymphangiogenic Remodeling and Lymphangiogenesis Revealed in Angiopoietin-2 Deficient and Vegfc Hemizygous Mice." Diss., The University of Arizona, 2008. http://hdl.handle.net/10150/195639.
Texte intégralRésumé :
Despite recent advances in lymphology, the molecular mechanisms regulating the development of the lymphatic system have not been fully delineated. Here I show that the growth factors Angiopoietin-2 (Ang2) and Vascular endothelial growth factor-c (Vegfc) serve distinct roles in the development of the lymphatic system.Adult Ang2-/- mice exhibit dermal lymphatic hypoplasia, abnormal smooth muscle cell (SMC) coverage of initial lymphatic vessels, and a severe deficiency of collecting lymphatic vessels. To determine whether these abnormalities were due to defects in the remodeling of the lymphatic vasculature, I characterized this process in Ang2-/- mice. Indeed, lymphatic vessels in the skin of Ang2-/- pups prematurely recruited SMCs and did not mature into collecting vessels during the remodeling stage of lymphatic development. In contrast, Ang2 knockout Ang1 knock-in mice did develop a hierarchal lymphatic vasculature, suggesting that activation of Tie-2 is required for normal lymphatic development. To further delineate the molecular mechanisms regulating lymphatic development, I also characterized Chylous ascites-3 (Chy-3) mice, a strain missing cytobands 8A4 to 8B3 from one copy of chromosome 8. Real-time PCR using genomic DNA demonstrated that the lymphangiogenesis gene, Vegfc, was included in the deleted region. All of the key components of a normal lymphatic network had developed in Chy-3 mice; however, the number of lymphatic vessels was reduced. Although the patterning of lymphatic vasculature in Chy-3 mice was altered, the architecture of the blood vasculature appeared normal. Ang2-/- and Chy-3 mice are grossly indistinguishable from one another; however, their underlying lymphatic defects are dramatically different. Ang2-/- mice exhibit defects in lymphangiogenic remodeling and lymphangiogenesis, whereas Chy-3 mice show a reduced capacity for lymphangiogenesis. I propose that Ang2 maintains lymphatic vessel plasticity by preventing SMC-lymphatic vessel associations so maturation can occur and facilitates lymphangiogenesis in the presence of Vegfc. This is analogous to Ang2's function on the blood vasculature where it is thought to destabilize SMC-blood vessel interactions and facilitate hemangiogenesis in the presence of Vegfa.Taken together, these findings further delineate the development of the lymphatic system and could provide translational clues relevant to the pathogenesis and treatment of clinical disorders of the lymphatic system.
5
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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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/.
Texte intégralRésumé :
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.<br>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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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.
Texte intégralRésumé :
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’angiogenèse<br>Inhibiting 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.
Texte intégralRésumé :
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/.
Texte intégralRésumé :
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.<br>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 enfants<br>The 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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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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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 significatif<br>This 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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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.<br>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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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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Colin, Maité [Verfasser], and Bernd [Akademischer Betreuer] Hohenstein. "Analyse von VEGF, VEGF-Aktivierung und VEGF-Rezeptorexpression bei humanen entzündlichen Nierenerkrankungen / Maité Colin. Betreuer: Bernd Hohenstein." Erlangen : Universitätsbibliothek der Universität Erlangen-Nürnberg, 2012. http://d-nb.info/1025963806/34.
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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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Shi, Shuning. "VEGF-A, VEGF-B and PIGF in mouse oxygen induced retinopathy /." St. Lucia, Qld, 2002. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17390.pdf.
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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.<br>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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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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Sattler, Florentine [Verfasser], Sabine [Akademischer Betreuer] Mihm, Jochen [Akademischer Betreuer] Gaedcke, and 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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Scheidegger, Patrick. "Targeting of human endothelial cells by VEGF and VEGF-like peptide mimetics /." [S.l.] : [s.n.], 2000. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=13667.
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Agreste, Fernanda Rodrigues. "Expressão espaço-temporal do sistema VEGF e do EG-VEGF no timo de cães." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/10/10132/tde-08122010-154007/.
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O objetivo deste trabalho foi avaliar a expressão de fatores de crescimento responsáveis pelo processo vasculogênico durante o desenvolvimento e involução do timo em cães. Para este propósito, timos de fetos de cães (30, 40 50 e 60 dias de desenvolvimento), cães jovens (6 meses de idade) e cães adultos (1 ano de idade) foram coletados. Os tecidos foram analisados estereológicamente e submetidos à imunohistoquímica, PCR tempo real e western blot para os componentes do sistema VEGF (VEGF-A, VEGF-C, Flt-1, KDR e Flt-4) e endocrine gland-derived (EG)-VEGF. Pela estereologia, observamos um aumento no número dos vasos durante o desenvolvimento do órgão e uma diminuição durante a involução (p<0.05). Todos os componentes do sistema VEGF e do EG-VEGF foram detectados em todos os estágios durante o desenvolvimento e involução. As proteínas correspondentes foram localizadas nas células endoteliais e células epiteliais da região cortical e medular, sendo que o EG-VEGF foi observado apenas nas células epiteliais da região medular. A expressão do RNAm do sistema VEGF e do EG-VEGF apresentou um perfil tempo-dependente durante o desenvolvimento e involução. O sistema VEGF apresentou uma expressão constante durante o desenvolvimento e um aumento progressivo durante a involução, com exceção do KDR que se mostrou crescente durante todo o período de desenvolvimento e involução e do VEGF-C que apresentou alta expressão durante a involução. A expressão do RNAm do EG-VEGF foi crescente durante as fases estudadas, já a expressão da sua proteína foi alta no início do desenvolvimento do timo e diminui na involução, onde permanece praticamente constante durante todo o período. Nossos resultados sugerem que o sistema VEGF e o EG-VEGF possuem atividades biológicas similares nas glândulas endócrinas e diferentes papéis durante o desenvolvimento e involução, o qual pode ser especificado em estudos futuros. Possíveis funções incluem um efeito modulatório na vasculogênese tímica e microambiente, influenciando na diferenciação e proliferação de timócitos, maturação de células T, interação célula-célula e secreção de hormônios tímicos.<br>The aim this study was therefore to evaluate the expression of growth factors responsible for the vasculogenic process throughout development and initial involution of the canine thymus. For that purpose, thymuses from fetuses (30, 40, 50 and 60 days), juvenile (6 months) and adult (1 year) dogs were collected. The tissues were examined stereologically and subjected to immunohistochemistry, Real Time PCR and western blot for components of the VEGF-system (VEGF-A, VEGF-C, Flt-1, KDR and Flt-4) and endocrine gland-derived (EG)-VEGF. By means of stereology, the total number of blood vessels increased during development and decreased during involution. These changes were statistically significant (p<0.05). All components of the VEGF-system and EG-VEGF were detected in all stages during development and involution. The corresponding proteins were localized in endothelial and epithelial cells of cortical and medullar regions, and EG-VEGF was detected only in epithelial cells of medular region. The VEGF-system and EG-VEGF protein and mRNA expression showed a specific time-dependent profile during development and involution. The VEGF system showed a constant expression during development and a progressive increase during involution, except KDR that showed increased during all development and involution and VEGF-C that showed high expression during involution. The EG-VEGF RNAm expression was increased during development and involution, but protein expression was high in early thymus development and decreased in involution, and remains constant during all period. Our results suggest that VEGF-system and EG-VEGF have similar biological activities in endocrine glands and different roles during thymus development and involution which have to be specified in further studies. Possible functions include a modulatory effect on thymic vasculogenesis and microenvironment, influencing thymocyte proliferation and differentiation, T-cell maturation, cell-cell interaction and thymic hormonal secretion.
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Gomes, Luana Pimenta. "Avaliação dos fatores de crescimento endotelial vascular VEGF e de seus principais receptores VEGFR-1 e -2 no processo de cicatrização com influência da radioterapia em ratos da linhagem Wistar." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5160/tde-05112013-125011/.
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Danos teciduais de qualquer natureza desencadeiam uma série de eventos que irão promover a regeneração ou a cicatrização do tecido lesado. Este reparo é um processo complexo que envolve a interação de diversos tipos celulares que são ativados por uma vasta gama de mediadores químicos, componentes da matriz extracelular, microorganismos e alterações físico químicas no microambiente da lesão e das áreas adjacentes. A participação do fator de crescimento endotelial vascular (VEGF) e de seus dois principais receptores (VEGFR-1 e -2) é de grande importância nos processos de cicatrização levando-se em conta a neovascularização. Após uma análise circunstanciada da literatura sobre os efeitos da radioterapia na neovascularização e a relação com a expressão do VEGF e VEGFR-1 e -2 na cicatrização observou-se que ainda há uma série de questões a serem investigadas. O objetivo desse projeto de pesquisa é estudar a expressão imuno-histoquímica do VEGF e VEGFR-1 e -2 e a densidade vascular sanguínea (DVS) após incisão e reparação cutânea em animais sob influência da radioterapia e em um período de aproximadamente seis meses. Neste estudo foram utilizados 60 ratos da linhagem Wistar distribuídos aleatoriamente em seis grupos (controle 3 e 6 meses, radioterapia pré-cirúrgica 3 e 6 meses, radioterapia pós-cirúrgica 3 e 6 meses). Após a eutanásia dos animais de acordo com os princípios bioéticos, foram retirados os espécimes alvo que foram avaliados macro e microscopicamente. O estudo imuno-histoquímico dos VEGFs foram realizados usando os anticorpos específicos supracitados nas diluições especificadas pelo fabricante, enquanto o estudo do DVS foi realizado com o anticorpo Von Willebrand Factor (VWF) que foi utilizado para marcar especificamente as células endoteliais. Nos períodos de tempo estudados, evidenciou-se a expressão significativa destes fatores de crescimento no tecido, na maioria dos casos. Os casos primeiramente irradiados apresentaram celularidade bizarra, com células gigantes e multinucleadas, estruturas do estroma hialinizadas e necrose imunomarcadas de moderada a forte para receptores de VEGF no endotélio e vasos sanguíneos. Essas características são consistentes com a literatura, uma vez que a forte relação do VEGFR-2 e a sua persistência na neovascularização e formação de tecido de granulação foram evidenciados. Os resultados mostraram que a expressão de VEGF é constantemente expressa em diferentes tempos da cicatrização de feridas e formação de cicatriz<br>Tissue damages of any nature unchain a series of events that will promote regeneration or healing of the injured tissue. This repair is a complex process that involves the interaction of various cells types. These cells are activated by a vast gamma of chemical mediators of the extracellular matrix, microorganisms and chemical and physical alterations in the injury microenvironment and adjacent areas. The participation of vascular endothelial growth factors (VEGF) and their two main receptors (VEGFR-1 and -2) has great importance in the healing process considering neovascularization. After a detailed analysis of the literature about radiotherapy effect in neovascularization and its relation with the expression of VEGF and VEGFR-1 and -2 in the healing, it was observed that there are many questions to be investigated. The objective of this study was to evaluate the immunohistochemical expression of VEGF and VEGFR-1 and -2 and sanguineous vessel density (DVS) after incision and cutaneous repairing in animals under influence of the radiotherapy at three and six months. This study used 60 Wistar rats randomly distributed in six groups: control, preoperative radiotherapy and postoperative radiotherapy, of 3 and 6 month each. The specimens evaluated macro/microscopically were removed after animal\'s sacrifice, in accordance to clinical ethics principles. The immunohistochemistry study of VEGFs were conducted using above-mentioned specific antibodies in manufacturer specified dilutions, while the study of the DVS was performed with the Von Willebrand Factor antibody (VWF) which was used to mark endothelial cells specifically. In both periods studied, surgical wound and radiation damages are similar in most cases. The primarily irradiated cases presented bizarre cellularity, multinucleated giant cells, stromal hyalinization structures, moderate to strong necrosis, overexpression of VEGF receptors in the endothelium and blood vessels in consequence of radiotherapy. These findings are in accordance to the literature, since the strong relationship between VEGFR-2 receptor and its persistence in neovascularization and granulation tissue formation were seen. Our results have shown that VEGF expression is constantly expressed in different times of wound healing and scar formation
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Onions, Karen. "The differential modification of glomerular endothelial cell glycocalyx by VEGF-A and VEGF-C." Thesis, University of Bristol, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.705456.
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Zanella, S. "SYNTHESIS OF PEPTIDOMIMETIC LIGANDS TARGETING CELL-SURFACE RECEPTORS INVOLVED IN TUMOR ANGIOGENESIS." Doctoral thesis, Università degli Studi di Milano, 2017. http://hdl.handle.net/2434/473075.
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In the first part of the Thesis, the synthesis of different classes of peptidomimetics targeting integrin receptors is described. Both simple ligands and drug conjugates were synthesized and tested to assess their biological activity. In cancer therapy, peptides and peptidomimetics targeting integrins are employed as carriers to deliver cytotoxic drugs at the tumor site, taking advantage of integrin over-expression on the surface of tumor cells. Within this frame, synthetic efforts have been focused on the synthesis and on the conjugation to the cytotoxic agent paclitaxel of isoDGR-based integrin ligands to effect drug-targeting to integrin over-expressing tumor cells.
The second part of the Thesis deals with the vascular endothelial growth factor receptors and their ligands. In particular, the interaction of VEGF-C with VEGFRs has been considered, focusing the attention on the reason why this growth factor was considered a privileged candidate for the preparation of a small library of VEGFR-selective peptides. These peptides have been synthesized by introducing systematic modifications in the natural portion of the growth factor and evaluated as VEGFR binders and anti-angiogenic agents in vitro.
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Hedeen, Heather A. "A Kinetic Study of anti-VEGF-A Polyclonal Antibodies and anti-VEGF-A ssDNA Aptamers." DigitalCommons@CalPoly, 2012. https://digitalcommons.calpoly.edu/theses/754.
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A new detection reagent that could possibly augment or replace antibodies research and diagnosis methods are aptamers. Aptamers are ssDNA, RNA or polypeptide constructs that function like active antibodies. Antibodies and aptamers both specifically bind to selected target molecules, and as such they enable the detection or targeting of the presence or absence of a specific antigen.
In order to ensure that ssDNA aptamers perform similarly to antibodies, anti-VEGF-A polyclonal antibody and anti-VEGF-A ssDNA aptamer were evaluated against vascular endothelial growth factor A (VEGF-A) using Surface Plasmon Resonance (SPR). It was hypothesized that the anti-VEGF-A aptamer had the same, if not better, binding kinetics than the anti-VEGF-A polyclonal antibody, and as such offers an ideal replacement for use in in field, real-time testing assays.
SPR revealed that both the polyclonal antibody and ssDNA aptamer bound the target antigen, VEGF-A. Additionally, from the SPR kinetic analysis, the anti-VEGF-A aptamer had KD values of 20-28 nM and the anti-VEGF-A antibody had KD values of 16-127 uM. The binding efficacy of the aptamer was several orders of magnitude better than that of the antibody. The aptamer was also stable in solution for a longer amount of time than the antibody, which denatured in solution after two weeks.
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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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Spatola, Agata. "Studio della funzione del VEGF in modelli sperimentali di cellule." Thesis, Università degli Studi di Catania, 2011. http://hdl.handle.net/10761/234.
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Il danno epatico e' causato da diversi fattori che agiscono in vari modi. Il fegato ha pero' un'ottima capacita' rigenerativa dovuta a diverse molecole che agiscono sulla neovascolarizzazione e/o sulla proliferazione epatocitaria. Una di esse e' il VEGF per cui noi abbiamo voluto studiarne alcuni aspetti. Abbiamo allestito modelli sperimentali di HepG2 trattate con etanolo e VEGF. In un secondo esperimento le abbiam trattate con etanolo e con surnatante di cellule HUVEC( trattate con VEGF). Quindi abbiamo studiato in microarray l'espressione di diverse famiglie geniche nelle HUVEC e nelle HepG2 rispettivamente trattate con VEGF e con sostanze epatotossiche. Infine, abbiamo studiato una proteina a funzione anti apoptotica, la smp30, come possibile fattore che potrebbe giocare un ruolo importante nella rigenerazione del fegato.<br>The hepatic damage is caused by different factors that operate in several ways. Liver,however,has a good capacity of regeneration, thanks to many molecules which act on neovascularization and/or on epatocytes proliferation.One of these molecules is VEGF so we decided to analise some aspects of its function.We worked on experimental models of HepG2 cells, treated with EtOH and VEGF and, in a second experiment, we treated them with EtOH and HUVEC cells surnatant (Previously, HUVEC were treated with VEGF). Than we used microarray to evaluate the genic espression of several gene families, after HUVEC and HepG2 treatment with, respectively, VEGF and several hepatotoxic substances. Finally, we have studied an anti-apoptotic protein,smp30, as a possible factor which can play an important role in hepatic regeneration.
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Klein, Johann [Verfasser]. "Kardiomyozytäre Effekte von VEGF / Johann Klein." Gießen : Universitätsbibliothek, 2012. http://d-nb.info/1064702996/34.
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Ourradi, Khadija. "Unravelling VEGF signalling in the lung." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.683728.
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Vascular endothelial growth factor (VEGF) is a potent mitogenic, angiogenic and permeability factor that has been associated with the development of lung disease. The VEGF gene undergoes alternate splicing of exon 8 to produce two isoform families with differing functional effects. VEGF16sa is the most biologically active member of the VEGFxxxa family. One member of the VEGFxxxb family, VEGF16Sb, has "inhibitory" effects on VEGF16sa induced endothelial proliferation, migration and permeability. This study is based upon the hypothesis that these isoforms utilise differing signalling pathways, identification of which would enable manipulation of their functional effects. To investigate this hypothesis, mRNA and protein expression of VEGF receptors and coreceptors in human pulmonary microvascular endothelial cells (HPMEC) were compared to those of systemic human umbilical vein endothelial cells (HUVEC). Potential downstream signalling pathways and mechanisms underlying VEGF165a and VEGF165b induced changes in cell permeability were investigated using signalling inhibitors and cellular distribution of the cell-junctions proteins VE-cadherin and ZO-l. Finally, PCR array profiles were utilised to screen potential differences in gene expression downstream ofVEGF and nitric oxide. The work presented shows that HPMEC and HUVEC cells differ in basal expression ofVEGF receptors and co-receptors, and that they are modified in response to chronic stimulation with VEGF isoforms. Cell signalling pathways downstream of VEGF-R2 differ between VEGF16sa and 16Sb and between the cell types. Three different methods (Endohm, ECIS and FITC-BSA passage) showed that VEGF16sa induced an increase and VEGF16Sb a decrease, in permeability for both HPMEC and HUVEC. L-NAME, L-NIO and PI3K (AKT leNOS pathways) inhibitors, blocked both VEGF isoforms suggesting no differential signalling in this pathway. Observation of changes in VE-cadherin and ZO-l expression pattern at cell junctions after VEGF16sa stimulation but not after VEGF16Sb suggested that this was a possible mechanism involved in the regulation of HPMEC and HUVEC permeability. PCR profiling array suggested some potential differential gene expression following VEGF16sa and VEGF16Sb stimulation. Understanding the signalling pathways utilised by VEGF isoforms to regulate lung biology could enable us to preferentially induce specific beneficial effects in the lung such as epithelial mitosis, whilst inhibiting detrimental effects such as increased permeability.
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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.<br>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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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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Füger, Andrea Sylvia [Verfasser]. "Die Bedeutung der Angio-, Lymphangiogenesefaktoren VEGF, VEGF-C und VEGF-D für die Genese und Progression des Zervixkarzinoms und ihr Nutzen für die Diagnostik desselben / Andrea Sylvia Füger." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2009. http://d-nb.info/1023582880/34.
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Almeida, Aroldo dos Santos. "Significado clínico da expressão de VEGF-C e de podoplanina em carcinomas espinocelulares de boca." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/25/25136/tde-02042009-103248/.
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A expressão do fator de crescimento endotelial vascular tipo C (VEGF-C) e de podoplanina pelas células malignas tem sido associada com a maior ocorrência de metástases regionais e/ou pior prognóstico para os pacientes com câncer de boca. O objetivo deste estudo foi avaliar o significado clinico da expressão de VEGF-C e podoplanina em 42 carcinomas espinocelulares (CEC) bem diferenciado de boca, com e sem comprometimento linfonodal, incluindo oito carcinomas verrucosos, tratados no Departamento de Cirurgia de Cabeça e Pescoço, do Hospital do Câncer A. C. Camargo, São Paulo, no período de 1980 a 2000. Os pacientes foram analisados quanto ao gênero, idade, cor, tabagismo, etilismo, localização do tumor primário, classificação pelo sistema TNM, tratamento, ocorrência de recidivas local e regional, metástase à distância, de segundo tumor primário, além da presença de infiltrações perineural, muscular, glandular e óssea e de embolizações vasculares. Analisou-se também o índice histopatológico de malignidade tumoral e as expressões imuno-histoquímica de VEGFC e de podoplanina pelas células malignas no front de invasão tumoral. A associação das expressões de VEGF-C e podoplanina com as variáveis estudadas foi calculada pelo teste quiquadrado. As probabilidades de sobrevida, acumuladas nos períodos de 5 e 10 anos calculadas pelo método de Kaplan-Meier e comparadas pelo teste de long-rank. A maioria dos CEC de boca, incluindo os carcinomas verrucosos, exibiu uma forte expressão de VEGF-C pelas células malignas. Houve uma tendência, sem associação estatisticamente significativa, dos pacientes com CEC de boca e forte expressão de VEGF-C apresentarem maior freqüência de recidivas locais e/ou regionais. A forte expressão de podoplanina foi significativamente associada com o gênero masculino (p=0,037), com o estadiamento T1 e T2 (p=0,037), com o estadio clínico I e II (p=0,027) e com a presença de infiltração glandular (p=0,003). As recidivas locais e regionais foram detectadas mais freqüentemente nos CEC de boca com forte expressão de podoplanina, porém sem diferença estatisticamente significativa, quando comparados com aqueles com expressão fraca da proteína. As taxas de sobrevida global e específica por câncer para os pacientes com tumores com forte expressão de VEGF-C e a taxa de sobrevida global para a forte expressão de podoplanina foram percentualmente menores do que aquelas dos pacientes com tumores com fraca expressão destas proteínas. O comprometimento linfonodal cervical se mostrou fator de prognóstico significativo (p=0,001) para os pacientes com câncer de boca. Estes resultados sugerem que a forte expressão de VEGF-C e podoplanina pelas células malignas juntamente com o comprometimento linfonodal regional são fatores indicativos de uma evolução clínica desfavorável e de um pior prognóstico para os pacientes com CEC bem diferenciados de boca.<br>The expression of vascular endothelial growth factor C (VEGF-C) and podoplanin by malignant cells has been associated with a greater incidence of regional metastasis and/or poor prognosis for patients with oral cancer. The purpose of this study was to evaluate the clinical significance of VEGF-C and podoplanin expression in 42 well-differentiated oral squamous cell carcinomas (OSCC), with and without lymph node involvement, including eight verrucous carcinoma, treated at the Department of the Head and Neck Surgery and Otorhinolaryngology, A. C. Camargo Cancer Hospital, São Paulo, from 1980 to 2000. Patients were evaluated according the following parameters: gender, age, ethnic group, tobacco and/or alcohol consumption, tumor location, TNM stage, treatment and clinical follow-up (recurrence, occurrence of a second primary tumor and death) and the presence of perineural, muscular, glandular and bone infiltrations or vascular embolizations. In addition, we investigated the histopathological malignancy index and the immunohistochemistry expression of VEGF-C and podoplanin by malignant cells in the invasive front tumor. Chisquare test or Fishers exact test was used to analyze the association of VEGF-C and podoplanin with demographic, clinical and microscopic variables in OSCC patients. The 5 and 10-year survival rates were calculated by Kaplan-Meier method and the comparison of the survival curves were performed using log rank test. Most of OSCC, including verrucous carcinoma, showed a high expression of VEGF-C by malignant cells. The OSCC patients with high expression of VEGF-C showed a tendency, without statistical significance, of local and/or regional recurrence. The overexpression of podoplanin was significantly associated with the male gender (p=0,037), with T1 and T2 stage (p=0,037), with I and II clinical stage (p=0,027) and with the presence of glandular infiltration (p=0,003). The local and regional recurrences were detected more frequently in OSCC with high expression of podoplanin, without statistical significant difference, when compared with those with low expression of the protein. The overall survival rates and cancer specific survival rates for OSCC patients with high VEGF-C expression and the overall survival rate for OSCC patients with podoplanin overexpression were lower than those of OSCC patients with low expression of these proteins. The cervical lymph node involvement was significant prognostic factor (p=0,001) for patients with oral cancer. These results suggest that the overexpression of VEGF-C and podoplanin by malignant cells and regional lymph node involvement are indicative factors of an unfavorable clinical outcome and a poor prognosis for patients with well-differentiated OSCC.
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Mallory, Bradford Paul. "The Pulmonary Vasculature Mediates Differential Time-Sensitive Effects on Embryonic Lung Development." University of Cincinnati / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1116510292.
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Treweeke, Andrew T. "Expression and function of VEGF and VEGF receptors in malignant B-cells from patients with chronic lymphocytic leukaemia." Thesis, University of Liverpool, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.425473.
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Biedermann, Katrin. "Generation and Charakterization of VEGF-E-mutants." Zürich : ETH, Eidgenössische Technische Hochschule Zürich, Departement Chemie und Angewandte Biowissenschaften, 2005. http://e-collection.ethbib.ethz.ch/show?type=dipl&nr=173.
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Müller, Susanne. "VEGF als Surrogatmarker des Therapieverlaufes der pAVK /." Regensburg, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000254395.
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Sköld, Mattias. "On VEGF and related factors in neurotrauma /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-986-2/.
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Warren, Simon. "VEGF-hämmare vid behandling av våt makuladegeneration." Thesis, Umeå universitet, Kemiska institutionen, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-80892.
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Brash, James Thomas. "VEGF isoforms and NRP1 in vascular hyperpermeability." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10058912/.
Texte intégralRésumé :
The cardiovascular system serves to deliver oxygen and nutrients to the tissues of the body whilst simultaneously removing waste products. Blood vessels display a degree of basal permeability to achieve this function, which is regulated at the level of the endothelial monolayer. In response to certain stimuli, the integrity of the endothelial barrier is reduced, rendering blood vessels hyperpermeable. Best known as a potent inducer of angiogenesis, the vascular endothelial growth factor (VEGF) was originally identified as a vascular permeability factor. In certain diseases, such as those characterised by ischemia, VEGF upregulation causes vascular hyperpermeability and pathological oedema. VEGF exists in three major isoforms, termed VEGF120, VEGF164 and VEGF188, which variably engage one or more of several VEGF receptors, termed VEGFR1, VEGFR2 and NRP1. A better understanding of the how the different VEGF isoforms engage their receptors and downstream signalling pathways to promote vascular hyperpermeability may help refine current therapeutic strategies to target VEGF-induced oedema. In this volume of work, I have studied VEGF induced vascular hyperpermeability from several perspectives. Using an in vivo model of vascular hyperpermeability, I have compared VEGF isoform potency and investigated which receptors are required by different VEGF isoforms to promote vascular leakage. Using tissue culture models of vascular endothelium coupled with biochemical techniques, I have determined how VEGF isoforms and their receptors affect known hyperpermeability signal transduction pathways. Specifically, I have shown that NRP1 and its cytoplasmic domain (NCD) impact two VEGF hyperpermeability signalling axes, and that the NCD interacts with proteins previously linked to endothelial tight junctions and paracellular permeability. Finally, I have examined the expression of VEGF isoforms in several disease models that are characterised by vascular hyperpermeability.
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Pawson, Elizabeth J. "VEGF gene therapy in experimental diabetic neuropathy." Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.702481.
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