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 EC (HUVEC) and endothelial colony-forming cells (ECFCs) from patients with severe VWD, we found that loss of VWF resulted in increased Angpt-2 expression through the positive feedback loop Angpt-2-Tie-2-Akt-FOXO1-Angpt-2. In the gut of VWF-deficient mice, Angpt-2 expression was increased, whereas Angpt-1 expression was decreased, suggesting that VWF regulates the Angpt/Tie2 balance in the gut. Moreover, the intestinal vasculature in the jejunum of VWF-deficient mice appeared abnormal, with hypersprouting and lumen formation defects. The findings reveal VWF-deficient mice as a model to study gut angiodysplasia. We investigated sprouting angiogenesis in vitro using a fibrin bead assay and found increased sprouting in VWF-deficient EC. We developed a 3-dimensional microfluidic model of angiogenesis and found that ECFCs from patients with severe VWD exhibit defective remodeling and abnormal lumen formation, reminiscent of the defects in the gut of VWF-deficient mice. Importantly, inhibition of Angpt-2 reduced sprouting in VWF-deficient HUVEC and normalized vascular remodeling in VWD-ECFCs, suggesting that Angpt-2 inhibitors may be effective in patients with VWD with GI bleeding and angiodysplasia.