ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery

Blood. 2017 Jul 6;130(1):11-22. doi: 10.1182/blood-2016-10-747089. Epub 2017 Apr 20.

Abstract

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 no in 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS13 Protein / genetics
  • ADAMTS13 Protein / metabolism*
  • Angiopoietin-2 / genetics
  • Angiopoietin-2 / metabolism
  • Animals
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / pathology
  • Galectin 3 / genetics
  • Galectin 3 / metabolism
  • Mice
  • Mice, Knockout
  • Stroke / genetics
  • Stroke / metabolism*
  • Stroke / pathology
  • Vascular Remodeling*
  • von Willebrand Factor / genetics
  • von Willebrand Factor / metabolism*

Substances

  • Angiopoietin-2
  • Galectin 3
  • Lgals3 protein, mouse
  • von Willebrand Factor
  • ADAMTS13 protein, mouse
  • ADAMTS13 Protein