Von Willebrand Factor Abnormalities Studied in the Mouse Model: What We Learned about VWF Functions

Abstract

Up until recently, von Willebrand Factor (VWF) structure-function relationships have only been studied through in vitro approaches. A powerful technique known as hydrodynamic gene transfer, which allows transient expression of a transgene by mouse hepatocytes, has led to an important shift in VWF research. Indeed this approach has now enabled us to transiently express a number of VWF mutants in VWF-deficient mice in order to test the relative importance of specific residues in different aspects of VWF biology and functions in an in vivo setting. As a result, mice reproducing various types of von Willebrand disease have been generated, models that will be useful to test new therapies. This approach also allowed a more precise identification of the importance of VWF interaction with subendothelial collagens and with platelets receptors in hemostasis and thrombosis. The recent advances gathered from these studies as well as the pros and cons of the technique will be reviewed here.

Figure 1

Description of the mechanism leading to hepatocyte-derived expression of foreign proteins following hydrodynamic injection with plasmid DNA.

Figure 2

Characteristics of VWF expression after hydrodynamic gene-transfer in VWF-deficient mice. A: Injection of 50 μg of plasmid pLIVE-mVWF cDNA resulted in plasmatic expression levels around 800% (100% being the plasma VWF levels measured in wild-type mice) and was stable for about two weeks. Expression levels can be highly operator-dependent. B: Platelet counts were recorded for a few days following hydrodynamic gene transfer and were shown to slightly decrease 24 hours after injection but were back to pre-injection levels after 3 days. C: Multimeric profile of plasma VWF produced by hepatocytes following hydrodynamic gene transfer.