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Title: The control of blood vessel formation and function through the Von Willebrand Factor-Angiopoietin 2 pathway : in vitro, in vivo and patient studies
Author: Smith, Koval Elrado
ISNI:       0000 0004 7657 5441
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Von Willebrand Factor (VWF) is a large glycoprotein synthesised by endothelial cells (EC) and megakaryocytes. Defects in VWF cause the most common inherited bleeding disorder in humans, Von Willebrand disease (VWD). Some patients with VWD present with vascular malformations in the gastrointestinal (GI) tract (angiodysplasia), which can lead to severe intractable bleeding. Angiodysplasia may be linked to the ability of VWF to regulate blood vessel formation. VWF drives the formation of Weibel Palade Bodies (WPB) which store a key regulator of angiogenesis and permeability, Angiopoietin 2 (Ang-2). In this study, I investigate how VWF controls vascular formation and function through Ang-2. Inhibition of VWF expression in ECs caused enhanced synthesis and release of Ang-2. In addition, ECs isolated from a patient with a severe quantitative defect in VWF (type 3 VWD) showed enhanced synthesis and release of Ang-2, confirming that VWF regulates Ang-2 storage and synthesis in ECs. I investigate whether VWF regulates Ang-2 in vivo, and find that Ang-2 expression is increased in the hearts but not lungs of VWF-deficient mice, indicating a tissue specific regulation. I then investigate the pathway though which VWF may regulate Ang-2 expression. I show that VWF controls Ang-2 synthesis through a pathway involving Akt phosphorylation and the transcription factor FOXO1. I demonstrate a role for atorvastatin in pharmacological manipulation of this pathway, which may be relevant for patients with angiodysplasia and therapeutic manipulation of Ang-2 levels. Inhibition of Ang-2 was able to normalise the VWF-dependent increase in in vitro vascular sprouting. In vivo, increased expression of Ang-2 in the heart of VWF-deficient mice correlates with enhanced vascularisation. Furthermore, cardiac vessels from VWF-deficient mice showed enhanced permeability compared to controls assessed by perfusion of low (4.4 x 103) molecular weight dextran. The results of this thesis provides evidence for the role of VWF in controlling angiogenesis via an Ang-2 dependent pathway. Thus may suggest a novel molecular mechanism which may contribute to VWD associated vascular malformations.
Supervisor: Randi, Anna ; Starke, Richard Sponsor: National Heart and Lung Institute ; British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral