Recombinant ADAMTS13 reduces tPA-induced cerebral hemorrhage after ischemic stroke in mice

• 作 者: Bing-QiaoZhao;WenyingFan;LixiangWang;PingCai;MengchenFan;
• 机 构: State Key Laboratory of Medical Neurobiology,Shanghai Medical College and Institutes of Brain Scienc
• 出 处: International Conference for Physiological Sciences 2012(201
• 发表日期: 2012年期

　　tPA is approved for treatment of ischemic stroke, but it increases the risk of hemorrhage.Evidence suggests that VWF plays a pivotal role in thrombus formation after stroke.By cleaving VWF, ADAMTS13protects mice from stroke.We found that intraventricular injection of tPA or VWF under nonischemic conditions resulted in significant increase in BBB permeability.In contrast, rADAMTS13 blocked tPA-induced BBB opening.BBB disruption following stroke was exacerbated by intravenous administration of tPA, but this was attenuated by injection of rADAMTS13.Correspondingly, tPA-associated hemorrhage after stroke was significantly reduced by rADAMTS13.The antihemorrhagic effect of rADAMTS13 was reversed by injection of VWF.We also observed that either rADAMTS13 or inhibitors of Akt and RhoA inhibited tPA-mediated upregulation of VEGF in vascular endothelium after stroke.Furthermore, rADAMTS13 downregulated tPA-induced activation of pAkt and RhoA.These findings demonstrate that the VWF-cleaving protease rADAMTS13 reduced tPA-induced hemorrhage by regulating BBB integrity, and suggest that this effect may occur through the Akt/RhoA mediated VEGF pathways.