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ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery

Haochen Xu, Yongliang Cao, Xing Yang, Ping Cai, Lijing Kang, Ximin Zhu, Haiyu Luo, Lu Lu, Lixiang Wei, Xiaofei Bai, Yuanbo Zhu, Bing-Qiao Zhao and Wenying Fan

Key points

  • ADAMTS13 controls key steps of vascular remodeling during stroke recovery.

  • rADAMTS13 enhances ischemic neovascularization and vascular repair.

Abstract

Angiogenic response is essential for ischemic brain repair. However, the mechanisms leading to postischemic neovascularization have not been established, and no therapies have been identified. The VWF-cleaving protease ADAMTS13 is required for endothelial tube formation in vitro. However, there is currently no in vivo evidence supporting a function of ADAMTS13 in angiogenesis. Here we show that mice deficient in ADAMTS13 exhibited significantly 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 and 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 VEGFR-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 suggest that recombinant ADAMTS13 is a putative therapeutic avenue for promoting stroke recovery.

  • Submitted October 20, 2016.
  • Accepted April 16, 2017.