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SPINA, CECILIA. "Emerging Evidences for a Protumorigenic Role of the Endothelin Axis Uncover New Therapeutic Targets in Multiple Myeloma." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2017. http://hdl.handle.net/10281/144189.
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Multiple Myeloma (MM) is a monoclonal tumor of bone marrow (BM) plasma cell (PC), usually associated with a number of disease manifestations, including skeletal damage, anemia and immunosuppression. Despite recent therapeutic advances and an increased patient life expectancy, MM still remains an incurable malignancy.
MM PC is characterized by a strong BM niche dependence, acquiring an autonomous capacity of growth only in the latter stages of disease. The endothelin (ET) axis is mainly composed of Endothelin-1 (ET-1), and 2 G-protein coupled receptors, the ET receptor A (ETAR) and ET receptor B (ETBR). In the last decades it has been demonstrated that the ET axis is able to promote the development and progression of tumor cells in an autocrine and/or paracrine fashion. Accordingly, recent experimental and clinical data obtained in solid tumors have evidenced the possibility of interfering with ET receptors (ETRs) - via specific antagonists - for therapeutic purposes. On the basis of these premises, primary aim of this study was to assess whether the ET axis may have a protumorigenic role in MM, therefore becoming a therapeutic target. The experimental evidences we obtained demonstrated that MM cell lines, primary MM PCs and BM microenvironment cells express ET-1 transcript and release the corresponding protein. Interestingly, while ETAR was constitutively expressed by PCs from healthy donors, primary malignant PCs and MM cell lines, ETBR was detected only on malignant PCs of 54 of the 100 patients enrolled in the study and in 3/5 MM cell lines. Interestingly, B lymphocytes isolated from healthy donors BM or peripheral blood (PB) or from MM patients PB, did express ETAR but not ETBR. Based on the evidence that the expression of ETBR was strictly connected to the neoplastic transformation, we next demonstrated an altered methylation status of the ETBR promoter gene in malignant PCs from ETBR-expressing MM patients and MM cell lines. The possibility of interfering with ETRs in MM was investigated in vitro using RPMI-8226 and U266 MM cell lines through the use of ETAR and ETBR selective antagonists. Both ETAR and ETBR antagonists, used alone and/or in combination, decreased RPMI-8226 and U266 cell lines viability. Based on these data we next evaluated the potential therapeutic significance in MM of Bosentan, a dual ETRs antagonist already used in clinical practice for pulmonary arterial hypertension. In agreement with our in vitro experiments, Bosentan appeared to be effective in inhibiting the viability of RPMI-8226 and U266 cell lines by reducing p-p44/42 MAPK. Furthermore, this action appeared to be synergic to that of bortezomib, a proteasome inhibitor drug already used in first-line treatment of MM.
Overall our data demonstrate that the ET axis is a potential therapeutic target in MM. Further data are awaited in order to establish the prognostic significance of the aberrant expression of ETBR in MM.
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Adner, Mikael. "Altered expression of contractile endothelin receptors in the vascular bed." Lund : Dept. of Internal Medicine, University of Lund, 1998. http://catalog.hathitrust.org/api/volumes/oclc/39103326.html.
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Irani, Soussan. "The Endothelin Axis and Angiogenesis in Papillary Thyroid Carcinoma." Thesis, Griffith University, 2014. http://hdl.handle.net/10072/366833.
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Papillary Thyroid Cancer (PTC) is the most common thyroid cancer accounting for 80% of all cases. The prognosis is good, with 5-year survival rates of 95%, but in some cases the tumour behaves in an aggressive manner characterized by local recurrence and/or metastasis, processes contributed to by angiogenesis.
Angiogenesis is an essential physiologic activity involved in normal tissue biology and several pathologic conditions such as cardiac failure, and cancer. During carcinogenesis, tumour cells secrete pro-angiogenic factors to initiate angiogenesis. Angiogenesis also causes the migration of endothelial cells from pre-existing vessels to improve nutrient and oxygen delivery to tumours, angiogenesis has a key role in tumour growth and metastasis.
Vascular endothelial growth factor (VEGF) has a pivotal role in the control of angiogenesis, aggressiveness in thyroid cancers. The endothelins (ETs) are a family of genes inducing DNA synthesis and cellular growth in different cells, affecting vascular tone and angiogenesis. ET-1 has a direct effect on neoplastic cells by inducing cellular proliferation, migration as well as invasion and inhibition of apoptosis. ET-1 induces VEGF expression by increasing hypoxia-inducible factor-1α (HIF-1α) stimulation.<br>Thesis (PhD Doctorate)<br>School of Medical Science<br>Griffith Health<br>Full Text
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Rabura, Sebastian. "Bedeutung der Endothelin-Plasmakonzentration für die Effektivität von inhalativem Stickstoffmonoxid im Modell des akuten Lungenversagens." Doctoral thesis, Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-137313.
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Das akute Lungenversagen ist gekennzeichnet durch eine schwere Störung des Gasaustausches mit ausgeprägter arterieller Hypoxämie. Die inhalative Gabe von Stickstoffmonoxid (iNO) erfolgt in der Therapie zur Verbesserung der arteriellen Oxygenierung, der Effekt ist jedoch variabel. Bisher existieren nur wenige Studien zur Identifikation von Faktoren, die die Effektivität von iNO bestimmen. Die positive Wirkung von iNO auf den Gasaustausch lässt eine Vasokonstriktion in beatmeten Lungenarealen vermuten. Wir untersuchten eine mögliche Wechselwirkung zwischen dem endogenen Vasokonstriktor Endothelin-1 (ET-1) und iNO in einem tierexperimentellen Modell des akuten Lungenversagens.
Sechzehn Schweine wurden narkotisiert, invasiv beatmet und nach Induktion des akuten Lungenschadens (ALI) mittels repetitiver Surfactantauswaschung (Lavagemodell nach Lachmann) zwei Gruppen zugeteilt. Die NO-Gruppe (n=8) erhielt eine Inhalation von 30ppm NO, die Kontrolltiere (CTR-Gruppe, n=8) blieben ohne weitere Intervention. Während der nächsten vier Stunden wurden Messungen von Gasaustausch und ET-1 Konzentrationen im arteriellen Blut durchgeführt. Bei allen Tieren führte die Induktion des ALI zu einer signifikanten Verschlechterung des Gasaustausches. Die Gabe von iNO bewirkte in der NO-Gruppe eine signifikante Erhöhung des PaO2. Die ET-1 Plasmaspiegel stiegen im Verlauf an und waren nach drei Stunden in der NO-Gruppe signifikant niedriger als in der CTR-Gruppe. Dabei zeigte sich eine signifikante, moderate Korrelation zwischen den ET-1 Plasmaspiegeln und den durch iNO induzierten Änderungen in PaO2 und Shunt.
Damit konnte ET-1 als ein Einflussfaktor auf die durch iNO induzierte Verbesserung des Gasaustausches identifiziert werden.
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Borrull, Aurélie. "Obtention et caractérisation d’anticorps monoclonaux dirigés contre les récepteurs des endothélines, ETAR et ETBR, surexprimés dans de nombreux cancers et impliqués dans la progression tumorale." Thesis, Paris 11, 2015. http://www.theses.fr/2015PA114820/document.
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Il est admis que l’axe endothéline (endothélines ET-1, -2 et -3 et leurs RCPG ETAR et ETBR), participe à la progression tumorale. Alors qu’ETAR est par exemple surexprimé dans le cancer de l’ovaire, ETBR l’est dans le mélanome. Cette surexpression, ainsi que l’implication d’ETA/BR dans la carcinogenèse, font de ces RCPG une cible tumorale pertinente. En raison de leurs forte spécificité, actions cytotoxiques variées, possibilités de couplage, les anticorps monoclonaux (AcM) sont des outils de choix en diagnostic et thérapie anti-cancéreuse. Cependant, on déplore actuellement l’absence d’AcM ciblant des RCPG sur le marché. Par une technique d’immunisation génique, 4 AcM anti-ETAR et 24 anti-ETBR ont été produits. Les résultats préliminaires obtenus avec les anti-ETAR sont prometteurs puisque ces AcM lient avec une haute affinité ETAR surexprimé dans des cellules CHO, l’un d’eux inhibant fortement la liaison du ligand. Mon travail de thèse s’est cependant concentré sur la caractérisation d’un anti-ETBR. Cet AcM reconnaît de façon spécifique et avec une forte affinité la conformation native d’ETBR surexprimé à la surface de cellules de mélanomes, suggérant l’existence d’une forme tumorale du récepteur. Suite à sa liaison aux cellules UACC-257 (lignée de mélanome), l’AcM se trouve internalisé. Dans ces cellules, malgré son incapacité à inhiber la liaison de l’ET, cet AcM inhibe l’activation de la voie PLC induite par le ligand et est également un fort inhibiteur de la migration due à l’activation de l’axe endothéline. Ces travaux soulignent l’intérêt de cet AcM comme outil diagnostique et thérapeutique dans le cas du mélanome<br>It has been admitted that endothelin axis (endothelins ET-1, -2 and -3 and related GPCRs ETAR and ETBR) is involved in tumor progression. For instance, while ETAR is overexpressed in ovarian cancer, ETBR is in melanoma. This overexpression, as well as ETA/BR involvement in carcinogenesis, make these GPCRs a relevant tumor target. Because of their high specificity, various cytotoxic actions, possibilities of coupling, the monoclonal antibodies (mAbs) are useful tools in diagnosis and anti-cancer therapy. However, the absence of mAbs targeting GPCRs on the market is regrettable. Thanks to DNA immunization, 4 anti-ETAR mAbs and 24 anti-ETBR mAbs were produced. Preliminary results obtained with anti-ETAR are promising since these mAbs bind ETAR overexpressed in CHO cells with high affinity, one of them being a potent inhibitor of ligand binding. However, the aim of my PhD research works focused on the characterization of one anti-ETBR. This mAb specifically recognizes with high affinity the native conformation of ETBR overexpressed on the surface of melanoma cells, suggesting the existence of a tumor-specific receptor. Following its binding on UACC-257 cells (melanoma cell line), the mAb is internalized. In these cells, despite its inability to inhibit ET binding, this mAb is able to inhibit the ligand-induced activation of PLC pathway and display a potent inhibition of endothelin axis-induced migration. This work highlights the interest of this mAb as a tool for diagnosis and therapy in melanoma
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Allard, Bertrand. "Production et caractérisation d’anticorps polyclonaux et monoclonaux ciblant les récepteurs des endothélines en vue d’une immunothérapie des cancers." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA114803/document.
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Le développement des anticorps monoclonaux thérapeutiques est en plein essor notamment à cause de leur bénéfice important pour le traitement des cancers. Cependant, à l’heure actuelle, aucun anticorps monoclonal sur le marché ou en phase III ne cible de RCPGs, en dépit de l’implication grandissante de ces récepteurs dans la carcinogenèse. Parmi les RCPGs les plus pertinents pour l’oncologie, souvent cités dans la littérature et dont certains inhibiteurs chimiques sont en phase clinique avancée, on trouve les deux sous-types de récepteurs des endothélines ETAR et ETBR. Dans ce contexte, mon projet de thèse a consisté à produire des anticorps monoclonaux capables de lier spécifiquement les récepteurs des endothélines, puis à les caractériser dans le but d’évaluer leur potentiel antitumoral. Grâce à une stratégie d’immunisation génique, un ensemble de 27 anticorps monoclonaux, tous spécifiques de la forme native d’ETBR, a été obtenu. Un de ces anticorps, nommé rendomab-B1, a fait l’objet d’une caractérisation précise et s’est révélé être un puissant inhibiteur allostérique d’ETBR. De plus, cette propriété antagoniste a permis de bloquer l’action autocrine antiapoptotique de l’ET-1 sur des cellules endothéliales vasculaires, suggérant ainsi que le rendomab-B1 pourrait être utilisé comme agent thérapeutique afin d’inhiber les effets tumorigènes liés à la suractivation de l’axe ET1/ETBR au niveau de l’endothélium vasculaire tumoral. Par ailleurs, le rendomab-B1 a également été testé sur des lignées de mélanomes humains ; l’absence de fixation de l’anticorps malgré la présence de récepteurs ETB fonctionnels à la surface de ces cellules suggère l’existence d’une forme moléculaire atypique du récepteur, potentiellement spécifique aux mélanomes. A la lumière de ces résultats, le rendomab-B1 apparaît comme un outil prometteur, à la fois pour l’étude structurale et fonctionnelle d’ETBR, mais aussi pour une éventuelle thérapie anticancéreuse. Enfin, les 26 autres anticorps monoclonaux anti-ETBR, actuellement en cours de caractérisation, constituent également des molécules potentiellement intéressantes pour un usage fondamental ou thérapeutique impliquant ETBR. Pour conclure, ces travaux ont démontré l’intérêt de la méthode d’immunisation génique pour la production d’anticorps monoclonaux anti-RCPGs à visée thérapeutique<br>For a decade, monoclonal antibodies have become increasingly important for the biotherapeutic management of cancer. However, none of the monoclonal antibodies currently on the market or in late stage clinical trial do target a G-protein coupled receptor in spite of the emerging role of these receptors in tumor progression. Among the therapeutically relevant GPCRs for oncology, the endothelin receptors (ETAR and ETBR) are particularly attractive considering their overexpression in a wide range of tumors and their involvement in various stages of tumorigenesis. In this context, my PhD project consisted in producing and characterizing monoclonal antibodies directed against endothelin receptors with a view to use them as anti-tumor agents. Using an original DNA immunization strategy, we produced a panel of 27 monoclonal antibodies which selectively recognized ETBR expressed at the surface of transfected cells. One of these antibodies, named rendomab-B1, was extensively characterized and proved to be a potent allosteric antagonist of ETBR. Moreover, rendomab-B1 was able to disrupt the autocrine ET1-mediated survival loop on vascular endothelial cells, suggesting that this antibody could be used to prevent the pro-tumorigenic effect due to ET-1 and ETBR upregulation in the tumor-surrounding endothelium. Furthermore, rendomab-B1 binding onto ETBR was also assessed on melanoma cell lines and revealed that a tumor-specific form of ETBR may exist, as illustrated by the poor fixation of rendomab-B1 on these cells in spite of the presence of functional ETB receptors. Together, these results present rendomab-B1 as promising agent, not only for the structural and functional study of ETBR, but also for its therapeutic modulation in the case of cancer for instance. Finally, the other 26 monoclonal antibodies, whose characterization is still ongoing, also constitute potential tools for fundamental or therapeutic applications involving ETBR. To conclude, this work has highlighted the relevance of the DNA immunization approach to generate monoclonal antibodies against the native form of GPCRs
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Miyoshi, Takashi. "The role of endothelial interleukin-8/NADPH oxidase 1 axis in sepsis." Kyoto University, 2011. http://hdl.handle.net/2433/142065.
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Sax, Michael John. "The CCL5-CCR5 Axis in Breast Cancer." Thesis, Griffith University, 2015. http://hdl.handle.net/10072/365646.
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Cancer is one of the leading underlying causes of death worldwide. Despite decades of research, cancer is predicted to be the leading cause of death by the year 2020. Anti angiogenic therapies that target the key signalling molecule, vascular endothelial growth factor (VEGF) have shown promise in the treatment of some solid tumours, resulting in increased progression-free survival times in patients. However, there are several significant problems with current anti-angiogenic therapies, such as the phenomenon of resistance. Tumours can be divided into those that are intrinsically nonresponsive to therapy, and those that do respond. However, for those tumours that do respond to therapy, an initial positive response (tumour regression) is followed by tumour re-vascularisation and rapid relapse. Secondly, anti-angiogenic therapies target normal physiological processes, including vascular homeostasis, wound healing and the immune system, leading to a range of potentially negative side effects, including death. Thus unravelling the biology of angiogenesis and developing new drug targets is a priority of current research. The C-C chemokine receptor 5 (CCR5) has been the subject of extensive research in the last few years. This is primarily because of its association with the pathology of disease, viral infection, and the immune response. However, while the main ligand for CCR5, C C chemokine ligand 5 (CCL5) is known to be upregulated in malignant breast cancer, little has been done to unravel the CCL5-CCR5 axis in breast cancer and its potential role as a driver of malignancy. Furthermore, while experimental evidence, including data from CCR5 knockout mouse, suggests a role for CCL5-CCR5 in neovascularisation, little has been done to study the potential role of CCL5-CCR5 in tumour angiogenesis, as well as implications CCL5-CCR5 signalling may have on clinical course in breast cancer.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>School of Medical Science<br>Griffith Health<br>Full Text
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Fang, Jennifer S., Brian G. Coon, Noelle Gillis, et al. "Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification." NATURE PUBLISHING GROUP, 2017. http://hdl.handle.net/10150/626459.
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Establishment of a functional vascular network is rate-limiting in embryonic development, tissue repair and engineering. During blood vessel formation, newly generated endothelial cells rapidly expand into primitive plexi that undergo vascular remodeling into circulatory networks, requiring coordinated growth inhibition and arterial-venous specification. Whether the mechanisms controlling endothelial cell cycle arrest and acquisition of specialized phenotypes are interdependent is unknown. Here we demonstrate that fluid shear stress, at arterial flow magnitudes, maximally activates NOTCH signaling, which upregulates GJA4 (commonly, Cx37) and downstream cell cycle inhibitor CDKN1B (p27). Blockade of any of these steps causes hyperproliferation and loss of arterial specification. Re-expression of GJA4 or CDKN1B, or chemical cell cycle inhibition, restores endothelial growth control and arterial gene expression. Thus, we elucidate a mechanochemical pathway in which arterial shear activates a NOTCH-GJA4-CDKN1B axis that promotes endothelial cell cycle arrest to enable arterial gene expression. These insights will guide vascular regeneration and engineering.
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Lindberg, Lars. "Endothelial function during ischemia-reperfusion and effects of inhalation of nitric oxide." Lund : Dept. of Anesthesiology and Intensive Care, University of Lund, 1996. http://catalog.hathitrust.org/api/volumes/oclc/38164585.html.
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Zygmunt, Peter. "Endothelium-dependent hyperpolarization and relaxation of vascular smooth muscle." Lund : Dept. of Clinical Pharmacology, Lund University, 1995. http://catalog.hathitrust.org/api/volumes/oclc/38253127.html.
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Haneef, Randa. "The Role of Human Cord Blood Endothelial Colony Forming Cell-Derived Extracellular Vesicles In Acute Kidney Injury (AKI)." Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37627.
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Acute kidney injury (AKI) is a sudden reduction in renal function, associated with a high mortality rate. The main cause of AKI is ischemia reperfusion injury. We previously found that administration of endothelial colony forming cells (ECFCs) or their derived exosomes protects ischemic renal cells against ischemia via paracrine action. Moreover, ECFC-derived exosomes are highly enriched with miRNA-486-5p, which protects against ischemia. Unexpectedly, ECFC infusion into mice with AKI attenuates renal endothelial cell proliferation. Therefore, we examined the role of ECFC-derived exosomes and microparticles (MPs) on endothelial cell angiogenic properties (proliferation and migration) in vitro, the pathways by which exosomes get internalized into endothelial cells, and the effects of miRNA-486-5p on endothelial cell migration. Results: ECFC-derived exosomes and MPs enhance endothelial cell proliferation in hypoxia and normoxia, and improve cellular migration. Finally, miRNA-486-5p plays a role in inducing HUVEC migration in normoxia. Conclusion: These findings indicate that ECFC-derived exosomes and MPs protect endothelial cells against ischemia by activating cellular migration, and that miRNA-486-5p plays a role in endothelial cell recovery after ischemia.
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Graham, U. "Endothelial function, the renin-angiotensin-aldosterone axis (RAAS) and hypertension : diagnostic strategies and therapeutic role of potassium supplementation." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.557606.
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There is limited evidence of the effect of potassium on endothelial function. Three studies suggest a beneficial effect. Potassium raises aldosterone which has a negative effect on cardiovascular health. We aimed to determine the effect of potassium on endothelial function and the renin-angiotensin-aldosterone system in patients with moderate cardiovascular disease risk. We investigated potential new diagnostic and therapeutic interventions in patients with primary hyperaldosteronism (P A). Lastly we reviewed the outcomes in patients with P A who underwent adrenal venous sampling (A VS). The first study was a randomised controlled crossover study with 40 patients at > 1 0% cardiovascular disease risk. Patients took either 64mmol potassium or placebo for 6weeks with 6week washout. Endothelial function was assessed using pulse wave analysis measuring change in augmentation index to endothelial dependent (salbutamol) and independent (GTN) vasodilation. The second study explored the diagnostic potential of the 250mcg synacthen test in 9 P A patients, 26 essential hypertensives and 26 normotensives. We explored the aldosterone response to gonadotrophin releasing hormone (GnRH) in 6 patients with P A and 15 controls. The final study was a retrospective review of A VS results and adrenalectomy outcomes in 100 patients with PA. Potassium significantly improved systolic blood pressure and but did not affect endothelial function. Plasma renin activity and aldosterone both increased with potassium. Patients with P A had an exaggerated response to synacthen and GnRH ,- compared to controls. Our retrospective analysis found a cortisol corrected aldosterone affected to unaffected adrenal ratio of>2.0 with concordant C'T fmdings accurately classified 95% of P A patients. With adrenalectomy, 97% of patients with unilateral disease had improved blood pressure. Potassium had no effect on endothelial function but lowered systolic blood pressure. The increase in aldosterone did not have a negative impact on the vasculature. The synacthen and GnRH tests offer potential new diagnostic and therapeutic options in P A.
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Bodelsson, Gunilla. "Endothelial and adrenergic vascular mechanisms in the female reproductive system." Malmö : Dept. of Obstetrics and Gynecology, University of Lund, Malmoe University Hospital, 1995. http://catalog.hathitrust.org/api/volumes/oclc/38161037.html.
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Paye, Julie Melissa Davis. "Effect of the Insulin-like Growth Factor (IGF) Axis on the Transport Properties of Endothelial and Epithelial Cells In Vitro." Diss., Virginia Tech, 2003. http://hdl.handle.net/10919/29071.
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The overall objective of this research consists of two main parts: (1) provide evidence that autocrine production of IGF-I modulates tight junction permeability and (2) demonstrate the ability of IGFBPs to regulate IGF-I delivery across cell layers. To meet the first objective, parental and IGF-I secreting bovine mammary epithelial cells were tested for cell layer permeability, tight and adherens junction proteins, IGF-IR, and a downstream signaling components of IGF-IR. In comparison with parental cells, IGF-I secreting cells had high levels of IGF-IRs, but low levels of the junction components E-cadherin, b-catenin, and occludin. The differences in parental and IGF-I secreting cells was not due to extracellular stimuli since inclusion of IGF-I, IGFBP-3, or co-culture with SV40-IGF-I cells did not alter the barrier properties of parental cells, suggesting that intracrine signaling may alter cell connectivity. The second objective focused on exogenous rather than endogenous IGF-I and the role of IGFBPs and IGF-IRs in ligand transcytosis. Bovine aortic endothelial cells (BAECs) cultured on surfaces optimized to minimize paracellular transport were utilized to investigate the kinetics involved in the transport of insulin-like growth factor-I from the apical side of confluent monolayers to the basolateral side. Binding competitors were used to determine the role of the cell surface insulin-like growth factor-I receptor (IGF-IR) and cell surface insulin-like growth factor binding proteins (IGFBPs) in this transport process. Although IGFBPs initially retard delivery of IGF-I, using a computation model, this report shows that pulse durations of less than 6 hrs resulted in enhanced delivery of IGF-I in the presence of IGFBPs, above that for delivery in the absence of IGFBPs. In addition, the model was utilized to identify key parameters to target when developing engineered growth factors for the treatment of diseases. It is shown that the sorting factions and internalization rates are reasonable targets for the design of engineered growth factors. Since the sorting fractions are dictated by binding affinities in the acidic environment of the endosomes, it may be beneficial to design and analog of IGF-I that is more resistant to changes in pH, similar to those develop from epidermal growth factor.<br>Ph. D.
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Ali, Sakina. "Rôle des vésicules extracellulaires dans la pathogenèse de la résistance à l’insuline dans le syndrome métabolique LPS-enriched small extracellular vesicles from metabolic syndrome patients trigger endothelial dysfunction by activation of TLR4." Thesis, Angers, 2020. http://bu.univ-angers.fr/Contact.
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Le syndrome métabolique (SMet) est un ensemble de troubles métaboliques associés à une dysfonction endothéliale et à une résistance à l’insuline. Grâce à leur cargaison qu’ils peuvent transférer d’une cellule à l’autre, les vésicules extracellulaires (VEs), incluant les grandes (lEVs) et les petites (sEVs) vésicules sont impliquées dans différentes voies de communication intercellulaire. Parmi toutes les recherches menées sur les VEs, l’étude de leur implication dans la physiopathologie des maladies métaboliques a mis en évidence de nombreuses communications intercellulaires délétères pour le système vasculaire et pour la signalisation de l’insuline. Les objectifs de mon projet de thèse étaient de caractériser les sEVs circulants de patients SMet et non-SMet, d’évaluer leur effet métabolique sur la fonction endothéliale et enfin d’analyser l’effet des lEVs et des sEVs sur les cellules et tissus cibles de l’insuline. Premièrement, nous avons montré que la concentration circulante des sEVs étaient positivement corrélées avec les critères du SMet, notamment l’obésité viscérale, l’hypertension, la résistance à l’insuline et la dyslipidémie. Nous avons montré que les SMet-sEVs, enrichies en LPS, sont impliqués dans le développement d’une dysfonction endothéliale via l’activation de la voie de signalisation de TLR4. Deuxièmement, nous avons démontré que les deux sous-types de VEs peuvent induire une résistance à l’insuline dans les organes périphériques via des mécanismes moléculaires différents. Ces résultats ont permis de mettre en évidence les voies moléculaires par lesquelles les VEs participent aux altérations métaboliques associées à la dysfonction endothéliale et à la résistance à l’insuline pendant le MetS<br>Metabolic syndrome (MetS),characterized by interconnecting metabolic disorders, is associated with endothelium dysfunction and insulin resistance. Thanks to their ability to transfer their cargo to recipient cells, extracellular vesicles (EVs), including large(lEVs) and small (sEVs) vesicles are involved indifferent intercellular communication pathways. Among the research conducted on EVs, the study of their involvement in the pathophysiology of metabolic diseases have highlighted numerous intercellular communication that are deleterious for the vascular system and for insulin pathways. My thesis project aims were to characterize circulating EVs from non-MetS and MetSpatients, to evaluate their metabolic effect on endothelial function, and to analyze lEVs andsEVs effects on insulin target cells and tissues. First, we shown that circulating concentration of sEVs were positively correlated with MetS criteriain cluding visceral obesity, hypertension, insulin resistance and dyslipidemia. We have shown that MetS sEVs, enriched with LPS, are involved in the development of endothelial dysfunction through the activation of the TLR4 signaling pathway. Second, we demonstrated that both subtype of EVs can induce insulin resistance in peripheral tissues via different molecular mechanisms.These results allow understanding the molecular pathways by which EVs participate in metabolic alterations associated with endothelial dysfunctions and insulin resistance during MetS
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Slebe, Concha Juan Felipe 1981. "The FoxA1/FoxA2-LIPG axis regulates beast cancer growth through changes in lipid metabolism." Doctoral thesis, Universitat Pompeu Fabra, 2014. http://hdl.handle.net/10803/299798.
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The Fox transcription factor family comprises FoxA1, FoxA2 and FoxA3, which regulate tissue development and metabolism. In breast cancer, FoxA1 together with estrogen receptor regulates tumor growth and luminal specification. However, it is still unclear whether other members of the FoxA family participate in breast cancer pathogenesis and whether they contribute to tumor metabolic dependence. Here we show that FoxA1 and FoxA2 expression is mutually exclusive across different human breast cancer cell lines. Although both transcription factors regulate different set of genes and biological responses, they promote in vitro and in vivo tumor growth through the expression of endothelial lipase (LIPG). LIPG is ubiquitously expressed across various breast cancer subtypes, as seen in human cell lines and primary tumors. Furthermore, it has the capacity to rescue the loss of FoxA factors regulating a network enriched in oncogenic and structural lipids known to mediate proliferation. These findings collectively reveal how the FoxA1/FoxA2-LIPG axis regulates a central hub of lipids required for the growth of breast cancer.<br>La familia de factores de transcripción FoxA está compuesta por FoxA1, FoxA2 y FoxA3. Estos factores regulan el desarrollo y el metabolismo de diversos tejidos. En cáncer de mama, FoxA1 media la acción de estrógenos y andrógenos regulando la especificación y el crecimiento del subgrupo luminal. No obstante, aún es desconocida la participación de los otros miembros de la familia en el desarrollo tumoral o su posible función en la dependencia metabólica de éstos. En esta tesis se describió que la expresión de los factores de transcripción FoxA1 y FoxA2 es mutualmente exclusiva en diferentes líneas celulares de cáncer de mama humanas. A pesar de que FoxA1 y FoxA2 controlan diferentes programas génicos y diferentes respuestas biológicas, ambos promueven el crecimiento tumoral in vitro e in vivo regulando la expresión de la enzima lipasa endotelial (LIPG). LIPG se expresa ubícuamente en líneas celulares humanas y tumores primarios de diferentes subgrupos de cáncer de mama. Además, LIPG es capaz de rescatar la pérdida de los factores FoxA regulando una red de lípidos oncogénicos y estructurales que median proliferación. Estos hallazgos revelan colectivamente que el eje FoxA1/FoxA2-LIPG regula un nicho central de lípidos que son necesarios para el crecimiento de cáncer de mama.
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Karlsson, Caroline. "Direct and endothelium-linked serotonergic control of vascular tone in human uterine and umbilical arteries." Lund : Dept. of Obstetrics and Gynaecology, University of Lund Malmö University Hospital, 1998. http://catalog.hathitrust.org/api/volumes/oclc/40420934.html.
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Karlsson, Håkan. "Influence of FK506 on certain aspects of lymphocyte activation and lymphocyte-endothelial cell interactions in vitro." Lund : Dept. of Medical Microbiology, Section of Clinical Immunology, Lund University, 1997. http://catalog.hathitrust.org/api/volumes/oclc/39799195.html.
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Camara, Abdouramane. "Control of lymphoid organ CD169+ macrophage differentiation by stromal cells through the RANK-RANKL axis." Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ102.
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Au-delà de leurs rôles de sentinelles, de reconnaissance du danger et d’initiation des réponses protectrices, les signaux et le mécanisme qui gouvernent la formation des macrophages CD169 + sinusoïdaux ganglionnaires sont mal connus. Au cours de ma thèse, j’ai montré que la cytokine Receptor Activator of NF-kB Ligand (RANKL) est requise pour la formation de ces macrophages dès l’embryogenèse jusqu’aux quatre semaines après la naissance. Celle-ci est contrôlée par les cellules endothéliales lymphatiques (LECs) activées par RANKL produite par les cellules mésenchymateuses. Chez l’adulte, les LECs activées par RANKL sont encore nécessaires pour la reconstitution des populations de ces macrophages en cas de déplétion transitoire induite par un stimulus inflammatoire. En complément à cela, j’ai aussi démontré l’importance générale du double signal RANKL & lymphotoxine LTα1β2 dans la formation des macrophages non-ostéoclastiques de la rate et de la moelle osseuse<br>Lymph node CD169 + sinusoidal macrophages are sentinel cells that recognize the danger signals and initiate the protective immune responses. However, the signals and the mechanism underlying their formation are not well known. During my thesis, I have shown that the cytokine Receptor Activator of NF-kB Ligand (RANKL) is required for their differentiation, starting from the embryogenesis up to four weeks after birth. The lymphatic endothelial cells (LECs) activated by RANKL expressed by mesenchymal cells form the niches for the primary differentiation of these macrophages. Yet, in adults, RANKL-activated LECs are required for their niche replenishment after transient depletion induced by an inflammatory stimulus. Beyond lymph node, my research has revealed a general requirement of the double signal RANKL & lymphotoxin LTα1β2 for the differentiation of non-osteoclastic CD169 + macrophages of spleen and bone marrow
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Chi, Chen Chia, and 陳佳琪. "Study on Endothelin Axis Involved in Macrophage-Induced Cancer Cells Metastasis." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/24446685129506317310.
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碩士<br>國防醫學院<br>生物及解剖學研究所<br>95<br>Adhesion of tumor cells onto vascular endothelial cells and subsequent transendothelial migration are essential steps for cancer cells to enter in or exit from the vessels and thus metastasize to different tissues/organs. Tumor-associated macrophages have been known to provide many aids on tumor metastasis and malignant progression. In this study, we provide evidence demonstrating that macrophage conditioned medium (MCM) was able to induce human breast cancer MCF-7 and nasopharyngeal carcinoma NPC-TW01 cells to migrate toward and furthermore adhere onto endothelial cells, and subsequently induced cancer cells to achieve transendothelial migration. MCM induced endothelin (ET)-1 production in human umbilical vein endothelial cells (HUVECs) a then cancer cells. MCM also induced ET receptor (ETR)-B in endothelial cells and ETR-A and ETR-B in MCF-7 and NPC-TW01 cells. The ET antagonists (anti-ET-1 antibody, BQ123 and BQ788) could be used to block MCF-7 and NPC-TW01 cells chemotaxis toward endothelial cells, adhesion onto endothelial cells and transendothelial migration, suggesting that paracrine interactions between ETs and ETRs could induce signaling pathways and downstream gene expression to elicit more interactions between MCF-7 cells, NPC-TW01 cells and endothelial cells. Our data further indicated that ET axis induced expression of integrins aM,b1,b2, and b3 in MCF-7/NPC-TW01 cells and expression of integrins aV,a5,b1,b2, and b3 and the counter ligands of integrins, such as ICAM-1, ICAM-2, VCAM-1, PE-CAM, E-selectin, and P-selectin, in HUVECs. Because MCM-induced transendothelial migration of MCF-7 cells and NPC-TW01 cells could be drastically abolished by antagonizing antibodies against these integrins, the expression of these adhesion molecules was suggested to be required for tumor cells intravasation and furthermore cancer metastasis.
Anti-interleukin-8 receptor antagonizing antibody, interleukin-6 or tumor necrosis factor-a soluble receptor, and inhibitors against NF-B, MEKK, p38MAPK, and JNK, were used for analyzing the effects of these cytokines and signal pathways induced by MCM. Our data suggested that macrophages were able to elicit tumor necrosis factor-a-dependent ET-1 expression in HUVECs, and induced ETR-A/ETR-B expression in cancer cells via the interleukin-8,TNF-a,ERK,NF-kB pathway.
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"The angiotensin converting enzyme 2 - angiotensin (1-7) axis protects endothelial function against oxidative stress in diabetes." 2013. http://library.cuhk.edu.hk/record=b5884510.
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Zhang, Yang.<br>Thesis (Ph.D.)--Chinese University of Hong Kong, 2013.<br>Includes bibliographical references (leaves 147-169).<br>Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.<br>Abstract also in Chinese.
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Catar, Rusan Ali [Verfasser]. "Proatherosklerotische Wechselwirkung von oxidativem Stress, Low-density-Lipoprotein, Angiotensin II und Endothelin-1 in humanen Endothelzellen / von Rusan Ali Catar." 2007. http://d-nb.info/98584826X/34.
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Wang, Shur-Jen. "Study of yolk sac-derived endothelial cells." 1996. http://catalog.hathitrust.org/api/volumes/oclc/35676527.html.
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Yu, Duonan. "Mouse yolk sac endothelial cells and their organ-specific differentiation." 1998. http://catalog.hathitrust.org/api/volumes/oclc/42895468.html.
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Vann, James M. "Staphylococcus aureus ingested by cultured bovine endothelial cells express cytotoxic activity." 1986. http://catalog.hathitrust.org/api/volumes/oclc/15694313.html.
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Nör, Jacques Eduardo. "The role of endothelial cell survival and death signals in angiogenesis." 1999. http://catalog.hathitrust.org/api/volumes/oclc/68803397.html.
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Cale, Jacqueline M. "Regulation of endothelial nitric oxide synthase by intracellular calcium and phosphorylation." 2005. http://catalog.hathitrust.org/api/volumes/oclc/64130091.html.
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King, Adam Gideon. "Estrogen induces uterine angiogenesis through the expression of vascular endothelial growth factor." 2002. http://catalog.hathitrust.org/api/volumes/oclc/50860308.html.
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Thesis (M.S.)--University of Wisconsin--Madison, 2002.<br>Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 118-135).
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Lam, Tim-Tak. "Interactions of angiotensin I with endothelial cells angiotensin-converting enzyme and angiotensin I binding /." 1985. http://catalog.hathitrust.org/api/volumes/oclc/12871496.html.
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Thesis (Ph. D.)--University of Wisconsin--Madison, 1985.<br>Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 171-191).
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Soden, Ryan Ivan. "Intracellular signaling in LTA-induced VEGF expression of dental pulp cells a dissertation submitted in partial fulfillment ... for the degree of Master of Science in Endodontics ... /." 2005. http://catalog.hathitrust.org/api/volumes/oclc/67878283.html.
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Gosink, Eric Christopher. "Calcium homeostasis and its role in the formation of vasoactive substances in porcine adrenal medulla endothelial cells." 1995. http://catalog.hathitrust.org/api/volumes/oclc/34406861.html.
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Koehler, Shannon M. "Pregnancy-specific changes in Ca²⁺ signaling in uterine artery endothelial cells derived from pregnant and nonpregnant ewes." 2005. http://catalog.hathitrust.org/api/volumes/oclc/70825440.html.
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Di, Tao. "The role of intracellular Ca2+ mobilization and extracellular signal-regulated kinases in mediating pregnancy-induced changes in the uterine artery endothelial vasodilator production." 2000. http://catalog.hathitrust.org/api/volumes/oclc/46590495.html.
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"The protective role of KLF2-UCP2 axis in restoration of endothelial function in type 2 diabetes: Kruppel樣因子2-解偶聯蛋白2信號軸保護二型糖尿病血管內皮功能的研究". 2015. http://repository.lib.cuhk.edu.hk/en/item/cuhk-1291436.
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Luo, Jiangyun.<br>Thesis Ph.D. Chinese University of Hong Kong 2015.<br>Includes bibliographical references (leaves 97-117).<br>Abstracts also in Chinese.<br>Title from PDF title page (viewed on 03, October, 2016).<br>Luo, Jiangyun.
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Ling, Ling. "Investigarion of Activated Phosphaidylinositol 3’ Kinase Signaling in Stem Cell Self-renewal and Tumorigenesis." Thesis, 2012. http://hdl.handle.net/1807/32815.
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The phosphatidylinositol 3' kinase (PI3K) pathway is involved in many cellular processes including cell proliferation, survival, and glucose transport, and is implicated in various disease states such as cancer and diabetes. Though there have been numerous studies dissecting the role of PI3K signaling in different cell types and disease models, the mechanism by which PI3K signaling regulates embryonic stem (ES) cell fate remains unclear. It is believed that in addition to proliferation and tumorigenicity, PI3K activity might also be important for self-renewal of ES cells. Paling et al. (2004) reported that the inhibition of PI3K led to a reduction in the ability of leukemia inhibitory factor (LIF) to maintain self-renewal causing cells to differentiate. Studies in our lab have revealed that ES cells completely lacking GSK-3 remain undifferentiated compared to wildtype ES cells. GSK-3 is negatively regulated by PI3K suggesting that PI3K may play a vital role in maintaining pluripotency in ES cells through GSK-3.
By using a modified Flp recombinase system, we expressed activated alleles of PDK-1 and PKB to create stable, isogenic ES cell lines to further study the role of the PI3K signaling pathway in stem cell fate determination. In vitro characterization of the transgenic cell lines revealed a strong tendency towards maintenance of pluripotency, and this phenotype was found to be independent of canonical Wnt signal transduction. To assess growth and differentiation capacity in vivo, the ES cell lines were grown as subcutaneous teratomas. The constitutively active PDK-1 and PKB ES cell lines were able to form all three germ layers when grown in this manner – in contrast to ES cells engineered to lack GSK-3. The resulting PI3K pathway activated cells exhibited a higher growth rate which resulted in large teratomas.
In summary, PI3K signaling is sufficient to maintain self-renewal and survival of stem cells. Since this pathway is frequently mutationally activated in cancers, its effect on suppressing differentiation may contribute to its oncogenicity.