Understanding the Role of von Willebrand Factor (VWF) in Angiogenesis and Angiodysplasia

von Willebrand factor (VWF) is a large multimeric glycoprotein essential for hemostasis, mediating platelet adhesion to sites of vascular injury and stabilizing coagulation factor VIII (FVIII) in circulation. Deficiency or dysfunction of VWF results in von Willebrand disease (VWD), the most common inherited bleeding disorder, as well as acquired von Willebrand syndrome (AVWS) which arises secondary to medical conditions. Beyond its classic hemostatic function, VWF also plays an important role in regulating blood vessel formation. In patients with VWD and AVWS, severe and recurrent gastrointestinal (GI) bleeding due to angiodysplasia is a significant cause of morbidity, and current VWF replacement therapies are often inadequate, with refractory bleeding in many cases. This highlights the need to better understand how abnormal VWF contributes to the formation of these fragile, dysplastic vessels. This thesis examined the role of extracellular high molecular weight multimers (HMWM) of VWF in modulating angiogenesis through complementary endothelial colony-forming cell (ECFC) models and in vivo murine studies and further explored whether VWF replacement can correct aberrant vessel formation. In vitro, ECFCs derived from Type 2A and Type 3 VWD patients, as well as an individual with AVWS from aortic stenosis, exhibited impaired adhesion, proliferation and migration, together with abnormal angiopoetin-2 (Ang-2) trafficking. siRNA-mediated VWF knockdown in control ECFCs reproduced these phenotypes, confirming the direct contribution of VWF to endothelial function. These findings demonstrate the dual importance of intracellular VWF, stored in Weibel-Palade bodies (WPB) and extracellular HMWM VWF in preventing abnormal angiogenesis. In vivo, VWF-knockout mice demonstrated enhanced vascularization, confirming VWF as a negative regulator of angiogenesis. Local delivery of recombinant human VWF (r-hVWF | VONVENDI®) enriched in HMWM into Matrigel plugs reduced neovascularization and improved vessel maturation, while systemic gene transfer of VWF failed to replicate these effects, thus, underscoring the necessity of endothelial-specific processing and storage. Taken together, the results presented in this thesis provide new insights into the role of VWF in modulating angiogenesis, offering further mechanistic evidence linking VWF abnormalities to angiodysplasia and a foundation for future translational strategies aimed at reversing vascular malformations in patients with VWD, AVWS and related disorders.

Department dc:contributor.department

Translational Medicine

Year dc:date.issued

2026

Author dc:creator

• Ocran, Edwin

Advisor dc:contributor.supervisor

• James, Paula

• von Willebrand factor (VWF)
• von Willebrand disease (VWD)
• Angiogenesis
• Angiodysplasia

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/1974/36185

OAI identifier oai:identifier

oai:queensu.scholaris.ca:1974/36185