Investigating the role of von Willebrand factor (VWF) in angiogenesis
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Authors
Selvam, Soundarya
Date
Type
thesis
Language
eng
Keyword
BOEC , angiogenesis , aortic stenosis , von willebrand disease , von willedrand factor
Alternative Title
Abstract
Gastrointestinal bleeding from angiodysplasia can be a debilitating problem for patients with defective or deficient von Willebrand factor (VWF). Studies have pointed to a regulatory role for VWF in vessel formation however, the mechanisms are not completely understood. We used endothelial cell models and VWF-deficient mice to explore how VWF and in particular VWF multimers regulate angiogenesis. Our main findings are that blood outgrowth endothelial cells (BOECs) from patients with inherited and acquired VWF abnormalities display aberrant angiogenesis, circulating VWF multimers negatively regulate cell proliferation, both intracellular and extracellular VWF are likely needed to modulate angiogenesis, and VWF-deficient mice have increased vessel formation.
We found abnormal angiogenesis in BOECs from patients with von Willebrand disease (VWD) and aortic stenosis (AS). VWD BOECs had abnormal storage and secretion of VWF associated with increased secretion of the pro-angiogenic molecule angiopoietin-2 (Ang-2), impaired cell migration, and increased proliferation of some patient cells. AS patients presented with VWF plasma defects including a loss of high molecular weight multimers (HMWM) prior to surgery relative to after, suggesting increased proteolysis pre-operatively in a shear-dependent manner. Correspondingly, BOECs isolated from AS patients before surgery were more proliferative than controls and had increased intracellular Ang-2.
A role for VWF HMWM in modulating cell proliferation is supported by the increased proliferation of BOECs from type 2A VWD and AS patients. Additionally, VWF-deficient cells cultured in the absence of circulating multimers were more proliferative than cells cultured in the presence of even 50% VWF multimers. However, regardless of the circulating VWF multimer content, in the absence of intracellular VWF, cell migration velocity and tubule formation remained unchanged. These observations indicate that both intracellular and extracellular VWF may be required to comprehensively influence angiogenesis.
Lastly, we confirmed that VWF has a negative regulatory role in angiogenesis in a mouse model. This was evidenced by the fact that Matrigel plugs from VWF-deficient mice and the ears of one-month old VWF-deficient mice were more vascularized than wild-type.
Collectively, these studies point to a multifaceted role for VWF in angiogenesis and expand our existing knowledge on the mechanisms by which VWF regulates vessel formation.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.