Background: Gastrointestinal (GI) bleeding from angiodysplasia is a common problem in patients with inherited and acquired abnormalities of von Willebrand Factor (VWF) and can be challenging to manage. Recent studies have demonstrated a negative regulatory role of VWF in angiogenesis.

Aims: To examine the effect of VWF replacement on in vivo angiogenesis in a mouse model of VWF‐deficiency.

Methods: The Matrigel plug assay was performed in 14 to 16-week old C57Bl/6 VWF knockout (KO) mice of both genders (N=9) that expressed VWF antigen (VWF:Ag) levels of ≥20U/ml at 48-hours following hydrodynamic injection with wild type (WT) murine VWF cDNA. 
On day eight post-hydrodynamic injection, Matrigel mixed with fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) was injected subcutaneously in the right back flank of each mouse. In the left back flank, an equal volume of Matrigel with phosphate buffered saline (PBS) was injected as a control. After 14 days, plugs were harvested and processed for hematoxylin and eosin (H&E) and immunohistochemical staining (IHC). Retro-orbital (RO) sampling was performed at specific timepoints during the 14 day incubation period, to assess VWF:Ag and multimer structure (Figure 1A).

Results: VWF:Ag dropped to undetectable levels by day 12 (day 5 of Matrigel incubation) following hydrodynamic injections (Figure 1B). While VWF multimers were observed, high molecular weight multimers (HMWM) were absent and there was loss of intermediate MWM with time. (Figure 1 C&D). Matrigel plugs supplemented with FGF and VEGF showed increased vascularization (55 ± 30 cells/mm²) compared to PBS controls (15 ± 14 cells/mm²; P < 0.01; Figure 2C).

Conclusions: Although hydrodynamic VWF replacement was successful but short-lived in VWF-deficient mice, liver expressed murine VWF was predominantly low MWM and did not prevent angiogenesis in the Matrigel plug assay. Further research is needed to evaluate the role of VWF in in-vivo angiogenesis.

(A) Experimental timeline (B) VWF:Ag levels (C) VWF Multimers and (D) Densitometric analysis of multimers(A) H&E (B) IHC images and (C) Endothelial cell (CD31+ staining) quantification of whole plugs from VWF-KO mice

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/evaluation-of-von-willebrand-factor-vwf-replacement-on-in-vivo-angiogenesis-in-vwf%e2%80%90deficient-mice/