Von Willebrand Factor Deficiency Impairs Angiogenesis via Angiopoietin-2: Relevance for Gut Angiodysplasia

Management of recurrent gastrointestinal (GI) bleeding is a clinical unmet need for patients with Von Willebrand disease (VWD) and is linked to the presence of gut vascular malformations (angiodysplasia). We previously demonstrated that von Willebrand factor (VWF) regulates angiogenesis and vascular integrity. VWF controls the storage of the angiogenesis regulator Angiopoietin-2 (Angpt-2) in endothelial cells (EC), suggesting a candidate for the genesis of angiodysplasia; however, no direct evidence of the role of Angpt-2 in VWF-dependent angiogenesis is available. Using VWF-deficient Human Umbilical Vein Endothelial Cells (HUVEC) and endothelial colony forming cells (ECFCs) from severe VWD patients, we find that loss of VWF results in increased Angpt-2 expression through the positive feedback loop Angpt-2-TIE2-AKT-FOXO1-Angpt-2. In the gut of VWF-deficient mice, Angpt-2 expression is increased whilst Angpt-1 expression is decreased, suggesting that VWF regulates the Angpt/Tie2 balance in the gut. Moreover, the intestinal vasculature in the jejunum of VWF-deficient mice appears abnormal, with hyper-sprouting and lumen formation defects. The findings reveal VWF-deficient mice as a model to study gut angiodysplasia. We investigate sprouting angiogenesis in vitro using a fibrin bead assay and find increased sprouting in VWF-deficient EC. We develop a 3D-microfluidic model of angiogenesis and find that ECFCs from severe VWD patients exhibit defective remodeling and abnormal lumen formation, reminiscent of the defects in the gut of VWF KO mice. Importantly, inhibition of Angpt-2 reduces sprouting in VWF-deficient HUVEC and normalises vascular remodeling in VWD ECFCs, suggesting that Angpt-2 inhibitors may be effective in VWD patients with GI bleeding and angiodysplasia.