VWF regulation of angiogenesis through multiple pathways: model. A model for multiple pathways likely to be involved in VWF regulation of angiogenesis. In EC, VWF is essential for the formation of WPB, organelles that store the growth factor Ang-2. Loss of intracellular VWF results in increased release of Ang-2 from WPB; Ang-2 binding to its receptor Tie-2 can synergize with VEGFR-2 signaling to destabilize blood vessels and promote angiogenesis. Thus loss of VWF could enhance angiogenesis via an Ang-2/Tie-2/VEGFR-2 pathway. Moreover, VWF released from WPB interacts with the adhesion receptor integrin αvβ3 and stabilizes its expression on the cell surface. In selected conditions, αvβ3 integrin is able to quench VEGFR-2 activity and downstream signaling, thus exerting a repressive effect on angiogenesis. Loss of VWF in EC results in decreased αvβ3 expression, which may cause enhanced VEGFR-2 signaling. Enhanced, deregulated VEGFR-2 signaling has been shown to cause dysfunctional angiogenesis leading to dysplastic blood vessels, similar to those described in angiodysplasia. Finally, WPB also store the carbohydrate-binding protein Gal-3. Gal-3 promotes angiogenesis through pathways that involve both αvβ3 and VEGFR-2; levels of Gal-3 are increased in brain microvasculature of VWF-deficient mice. Thus, VWF is likely to affect multiple angiogenic pathways, both as an extracellular ligand and because of its ability to control storage and possibly expression of endothelial proteins. VEGFR-2, VEGF receptor-2.