on January 10, 2008
Published online before print January 10, 2008, doi: 10.1161/ATVBAHA.107.159442
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Submitted on August 13, 2007
Accepted on December 20, 2007
Correction of Bleeding Symptoms in von Willebrand Factor–Deficient Mice by Liver-Expressed von Willebrand Factor Mutants
Isabelle Marx ;
From the Institut National de la Santé et de la Recherche Médicale (INSERM) U770 (I.M., T.A., O.D.C., C.V.D.), Le Kremlin-Bicêtre, F-94276 France; Univ Paris-Sud, Le Kremlin-Bicêtre, F-94276 France; and the Laboratory for Thrombosis and Haemostasis (P.J.L., R.P.), Department of Clinical Chemistry & Haematology, University Medical Center Utrecht, The Netherlands.
* To whom correspondence should be addressed. E-mail: denis{at}kb.inserm.fr.
Objective—von Willebrand Factor (vWF) structure-function relationship has been studied only in vitro. To investigate the physiological importance of particular vWF domains, we have introduced mutations into murine vWF (mvWF) cDNA inhibiting vWF binding to glycoprotein (Gp) Ib, GpIIbIIIa, and to fibrillar collagen.
Methods and Results—We delivered wild-type (WT) or mutant mvWF cDNA into vWF-deficient (Vwf-/-) mice using hydrodynamic injection and assessed whether hemorrhagic symptoms could be corrected. Hydrodynamic gene transfer resulted in high expression of plasma mvWF 24 hours after injection (438±63% for 50 µg of cDNA). Factor VIII activity was normalized in Vwf-/- mice injected with mvWF cDNA and multimerization was achieved. Bleeding time was corrected after injection of WT mvWF cDNA in Vwf-/- mice whereas noninjected mice did not stop bleeding. Injection of the GpIIbIIIa and the collagen binding mutants in Vwf-/- mice also resulted in a correction of bleeding time whereas mice injected with the GpIb binding mutant were bleeding for as long they were observed, although blood loss was decreased compared with noninjected mice (61±21 µL versus 232±63 µL).
Conclusion—Our model allows the rapid in vivo evaluation of specific mutations on plasma vWF function.
Key words: von Willebrand disease • animal model • vWF • bleeding • hydrodynamic injection
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