Anti-inflammatory and anti-coagulant function of ADAMTS13 expressed under blood flow

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The function of von Willebrand factor(VWF) is essential for normal hemostasis and regulated by ADAMTS13 which cleaves VWF to smaller less-active forms. We recently found that ADAMTS13 limits thrombus growth at the on-going thrombus generation process, leading speculation that the excessive function of VWF mediated by ADAMTS dysfunction may link to arterial thrombosis in the microcirculation in many diseases.We investigated the effects of ADAMTS13 on ischemia-reperfusion injury using a 30-minute middle cerebral artery occlusion(MCAO) model in Adamts13-/-and wild-type mice. After reperfusion, the regional cerebral blood flow in the ischemic cortex was decreased markedly in Adamts13-/-mice compared to wild-type mice, which also resulted in a larger infarct volume for Adamts13-/-. Furthermore, brain ischemia induced more prominent activation of inflammatory cells co-expressing high-mobility group box1(HMGB1) and myeloperoxidase(MPO) in the cortical ischemic penumbra of Adamts13-/-mice. Thus, Adamts13 gene deletion aggravated ischemic brain damage, suggesting that ADAMTS13 may protect the brain from ischemia and inflammation by regulating VWF-platelet interactions after reperfusion.Moreover, a recombinant human ADAMTS13 infused to wild type mice before 4 hours' occlusion significantly reduced infarct volume without cerebral bleeding complications. These results indicate that ADAMTS13 could be an anti-inflammatory and anti-coagulant agent for prevention or treatment for many diseases, especially for stroke.