Von Willebrand Factor in Angiogenesis and Angiodysplasia

Abstract von Willebrand factor (VWF) is best known for its key role in haemostasis, capturing platelets at sites of endothelial damage and acting as carrier for coagulation Factor VIII. The importance of VWF in haemostasis is illustrated by the fact that its deficiency and/or abnormality causes von Willebrand disease (VWD), the most frequent inherited bleeding disorder, whilst raised levels of VWF are associated with an increased risk of arterial thrombosis. VWF is synthesized in megakaryocytes and in endothelial cells from most, but not all, vascular districts. Besides the well characterized binding to Factor VIII and with platelet receptors, VWF can interact with a plethora of proteins, from extracellular matrix components to growth factors and even DNA, suggesting that VWF may influence multiple processes. Moreover, VWF is required for the formation of Weibel Palade Bodies (WPB), endothelial storage organelles which contain many vascular regulators. It is therefore likely that this large protein, critically located at sites of vascular injury, is able to influence several vascular functions. Indeed over the last two decades novel functions for VWF in the vasculature have been identified, including the ability to modulate blood vessel formation. Studies in a mouse models of severe VWF deficiency have shown constitutively enhanced vascular networks in selected tissues, and enhanced angiogenesis in Matrigel and in response to ischemia in the brain. Moreover, studies on circulating endothelial progenitors from patients with type 3 VWD and lack of VWF synthesis have shown enhanced in vitro angiogenesis. The ability of VWF to regulate angiogenesis has clinical implications for a subset of VWD patients with severe, intractable gastrointestinal (GI) bleeding due to vascular malformations, called angiodysplasia. These lesions, found in patients with congenital VWD and acquired von Willebrand syndrome (AVWS), can cause severe gastrointestinal bleeding, often unresponsive to conventional replacement therapy. Therefore, understanding the mechanisms through which VWF modulates blood vessel formation is likely to have direct implications for the treatment of these patients. In vitro and in vivo studies indicate that VWF can regulate angiogenesis through multiple pathways. Strong candidates for this role are VWF binding partners, such as integrin αvβ3, and components of Weibel Palade bodies (WPB), such as Angiopoietin-2 and Galectin-3, whose storage is regulated by VWF. Several of these pathways converge on the master regulator of angiogenesis, also essential for maintaining endothelial homeostasis, namely the vascular endothelial growth factor (VEGF) pathway. Multiple regulators may act in concert, their relevance differing in congenital VWD vs acquired AVWS. Interestingly, recent studies in mouse models suggest that the roles of VWF may be tissue-specific. If confirmed, this will have important implications for the translational and clinical implications of these findings for patient with VWD. In summary, the finding that VWF is able to regulate blood vessel formation has opened a new area of research for this incredibly interesting and versatile protein, one which has profound implications for the treatment of patients with VWD and AVWS. Disclosures Randi: LFB: Other: Invited to one advisory board meeting 2018, Patents & Royalties, Research Funding, Speakers Bureau; Shire: Honoraria.