ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery
ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery
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ADAMTS13 通过改变中风恢复期间 VWF 反应性来控制血管重塑
DOI：
10.1182/blood-2016-10-747089
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发表时间：
2017-07-06
期刊：
影响因子：
20.3
通讯作者：
Fan, Wenying
中科院分区：
文献类型：
--
作者：
Xu, Haochen;Cao, Yongliang;Fan, Wenying
血管生成反应是缺血性脑修复的必要条件。von Willebrand factor (VWF)-具有血小板反应蛋白I型motif的切割蛋白酶崩解素和金属蛋白酶13成员（ADAMTS13）是体外内皮管形成所必需的，但目前没有体内证据支持ADAMTS13在血管生成中的功能。本研究表明，ADAMTS13缺失小鼠在中风后14天表现出新生血管、脑毛细血管灌注、微血管周细胞和平滑肌细胞覆盖减少、紧密连接和基底膜蛋白表达减少、血脑屏障（BBB）分解加速以及梗死周围皮层血清蛋白的血管外沉积。缺乏VWF或抗VWF抗体治疗可显著增加Adamts13（-/-）小鼠微血管、灌注毛细血管长度，逆转周细胞损失和血脑屏障改变。此外，我们观察到ADAMTS13缺乏降低了离体脑微血管中血管生成素-2和半乳糖凝集素-3的水平，而VWF缺乏则具有相反的效果。与此相关的是，在Adamts13（-/-）小鼠中，通过腺病毒处理或重组半乳糖凝集素-3过度表达血管生成素-2，使微血管减少、周细胞损失和血脑屏障破坏正常化。血管内皮生长因子受体-2拮抗剂SU1498可消除血管生成素-2过表达和重组半凝集素-3处理引起的Adamts13（-/-）小鼠血管变化。重要的是，在中风后7天用重组ADAMTS13治疗野生型小鼠，可显著增加新生血管和血管修复，并在第14天改善功能恢复。我们的研究结果表明，ADAMTS13控制着缺血性血管重构的关键步骤，重组ADAMTS13是促进中风恢复的一种假定的治疗途径。
Angiogenic response is essential for ischemic brain repair. The von Willebrand factor (VWF)-cleaving protease disintegrin and metalloprotease with thrombospondin type I motif, member 13(ADAMTS13) is required for endothelial tube formation in vitro, but there is currently noin vivo evidence supporting a function of ADAMTS13 in angiogenesis. Here we show that mice deficient in ADAMTS13 exhibited reduced neovascularization, brain capillary perfusion, pericyte and smooth muscle cell coverage on microvessels, expression of the tight junction and basement membrane proteins, and accelerated blood-brain barrier (BBB) breakdown and extravascular deposits of serum proteins in the peri-infarct cortex at 14 days after stroke. Deficiency of VWF or anti-VWF antibody treatment significantly increased microvessels, perfused capillary length, and reversed pericyte loss and BBB changes in Adamts13(-/-) mice. Furthermore, we observed that ADAMTS13 deficiency decreased angiopoietin-2 and galectin-3 levels in the isolated brain microvessels, whereas VWF deficiency had the opposite effect. Correlating with this, overexpression of angiopoietin-2 by adenoviruses treatment or administration of recombinant galectin-3 normalized microvascular reductions, pericyte loss, and BBB breakdown in Adamts13(-/-) mice. The vascular changes induced by angiopoietin-2 overexpression and recombinant galectin-3 treatment in Adamts13(-/-) mice were abolished by the vascular endothelial growth factor receptor-2 antagonist SU1498. Importantly, treating wild-type mice with recombinant ADAMTS13 at 7 days after stroke markedly increased neovascularization and vascular repair and improved functional recovery at 14 days. Our results suggest that ADAMTS13 controls key steps of ischemic vascular remodeling and that recombinant ADAMTS13 is a putative therapeutic avenue for promoting stroke recovery.