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. 2009 Oct 8;114(15):3329-34.
doi: 10.1182/blood-2009-03-213264. Epub 2009 Aug 17.

von Willebrand factor-cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke

Bing-Qiao Zhao  1 , Anil K Chauhan, Matthias Canault, Ian S Patten, Janie J Yang, Michael Dockal, Friedrich Scheiflinger, Denisa D Wagner
Affiliations

von Willebrand factor-cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke

Bing-Qiao Zhao et al. Blood. .

Abstract

Stroke is a leading cause of death and disability. The only therapy available is recombinant tissue plasminogen activator, but side effects limit its use. Platelets play a crucial role during stroke, and the inflammatory reaction promotes neurodegeneration. von Willebrand factor (VWF), an adhesion molecule for platelets, is elevated in patients with acute stroke. The activity of VWF is modulated by ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats-13) that cleaves VWF to smaller less-active forms. We recently documented that ADAMTS13 negatively regulates both thrombosis and inflammation. We report that deficiency or reduction of VWF reduces infarct volume up to 2-fold after focal cerebral ischemia in mice, thus showing the importance of VWF in stroke injury. In contrast, ADAMTS13 deficiency results in larger infarctions, but only in mice that have VWF. Importantly, infusion of a high dose of recombinant human ADAMTS13 into a wild-type mouse immediately before reperfusion reduces infarct volume and improves functional outcome without producing cerebral hemorrhage. Furthermore, recombinant ADAMTS13 did not enhance bleeding in a hemorrhagic stroke model. Our findings show the importance of VWF in regulating infarction and suggest that recombinant ADAMTS13 could be considered as a new therapeutic agent for prevention and/or treatment of stroke.

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Figures

Figure 1
Figure 1
Level of VWF regulates infarct volume after ischemic stroke in mice. Representative TTC stain of coronal brain sections of 1 mouse for each strain 22 hours after MCAO (top) and brain infarct volumes (bottom) in WT, VWF+/−, and VWF−/− mice. Deficiency or heterozygosity of VWF resulted in a significant decrease in infarct volume compared with WT.
Figure 2
Figure 2
ADAMTS13 regulates infarct volume after ischemic stroke in mice. Representative TTC stain of coronal brain sections of 1 mouse for each strain 22 hours after focal cerebral ischemia in WT, Adamts13−/−, and Adamts13−/−/VWF−/− (top) and corresponding brain infarct volumes quantification (bottom). Increase in infarct volume in Adamts13−/− mice, compared with WT, depended on the presence of VWF.
Figure 3
Figure 3
r-hu ADAMTS13 reduces infarct volume after focal cerebral ischemia in WT mice. Representative TTC staining of coronal brain sections of 1 mouse for each treatment and infarct volumes 22 hours after focal cerebral ischemia in mice treated with (A) vehicle or r-hu ADAMTS13 (derived from HEK293 cells) and (B) vehicle or r-hu ADAMTS13 (derived from CHO cells) are shown.
Figure 4
Figure 4
r-hu ADAMTS13 improves performances in the tape removal test after ischemic stroke. Time needed to remove tapes from both the contralateral and ipsilateral paws was recorded on sham-operated mice and mice that underwent MCAO (1 hour) injected intravenously with r-hu ADAMTS13 or vehicle 10 minutes before reperfusion. Global differences between groups were found for each parameter (P < .05).
Figure 5
Figure 5
Effect of the r-hu ADAMTS13 preparations on cerebral hemorrhage and tail bleeding time. (A) Representative unstained coronal brain sections of 1 mouse for each treatment show a lack of hemorrhage in r-hu ADAMTS13-treated mice (derived from HEK 293 and CHO cells). (B) Bleeding time measurements show highly increased bleeding in VWF−/− mice compared with WT mice. All the VWF−/− mice were cauterized at 900 seconds to stop bleeding. r-hu ADAMTS13-treated mice (5 hours) had a bleeding time comparable with WT mice (prepared in HEK cells) or prolonged bleeding time (prepared in CHO cells) but significantly shorter than the VWF−/− mice. n = 8 each group.
Figure 6
Figure 6
Effect of r-hu ADAMTS13 infusion on intracerebral hemorrhage after stroke in thrombocytopenic mice and mice with normal platelet count. (A) Supernatants of right (injured) hemisphere homogenates. (B) Hemorrhage volume as determined by hemoglobin brain tissue analysis. Hemoglobin level (corresponding to a volume of blood in μL) was determined in the right infarcted hemisphere. The levels of hemoglobin from the right hemispheres with normal platelet count were low (the same as in the noninjured left hemispheres whether platelet depleted or not depleted; not shown). In contrast, hemorrhage was significant in the right hemispheres of platelet-depleted mice. Infusion of r-hu ADAMTS13 did not affect the hemorrhage volume.
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