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Blockade of endothelial Notch signaling in cellular systems and adult mice

Berger, Caroline

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Angiogenesis is a fundamental process during embryogenesis, inflammation and wound healing. The formation of new vessels is coordinated by proteins of the VEGF and the Notch signaling cascades. Dysfunction of the precisely balanced crosstalk between Notch and VEGF signaling entails the formation of a non-functional vascular network. These imbalances play a critical role during progression of many diseases including atherosclerosis and tumor growth. Blocking of Notch signaling, by small molecule inhibitors or DLL4-specific antibodies, perturbs tumor perfusion and inhibits tumor growth in animal models. This study aimed to gain deeper insight into the complex function of Notch signaling in the endothelium. For this purpose, small soluble Notch ligand and receptor peptides were generated, which consist of the respective interaction domains only. Furthermore, the effects of deleting endothelial Notch signaling in adult mice were investigated. Application of the designed soluble DLL1, DLL4, and JAG1 ligands, as well as, the soluble NOTCH1 receptor blocked Notch signaling in endothelial and myogenic cells. All soluble ligands consistently exerted pro-angiogenic effects in vitro. The effects of DLL1 and DLL4 were markedly stronger than that of the JAG1 ligand and could also evoke elevated sprouting angiogenesis in the retina of newborn mice. Treatment with the soluble Notch receptor reduced endothelial sprouting in vitro. However, in vivo application of soluble NOTCH1 receptor protein resulted in increased retinal sprouting with elevated numbers of tip cells. Thus, the soluble ligands suppressed Notch receptor activity by acting as competitors for endogenous membrane-bound ligands; whereas the soluble receptor acted as a decoy for the different Notch ligands. Genetic studies with adult mice after endothelial-specific deletion of Notch signaling were performed. These mice developed cardiomyopathy within a few months; whereas vascular tumors developed after one year. In an ApoE-deficient model of hyperlipidemia, the deletion of endothelial Notch signaling improved the glucose tolerance of mice, but caused development of steatohepatitis. Thus, Notch signaling in the adult vasculature could be identified as a critical regulator of organ homeostasis as well as glucose and fat metabolism.

Item Type: Dissertation
Supervisor: Hofmann, Prof. Dr. Ilse
Date of thesis defense: 8 February 2013
Date Deposited: 13 Mar 2013 06:14
Date: 2013
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
Uncontrolled Keywords: Angiogenese Delta-Notch Signalweg
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