Activation of Frizzled-7 attenuates blood-brain barrier disruption through Dvl/β-catenin/WISP1 signaling pathway after intracerebral hemorrhage in mice

Fluids Barriers CNS. 2021 Sep 26;18(1):44. doi: 10.1186/s12987-021-00278-9.

Abstract

Background: Destruction of blood-brain barrier (BBB) ​​is one of the main mechanisms of secondary brain injury following intracerebral hemorrhage (ICH). Frizzled-7 is a key protein expressed on the surface of endothelial cells that controls vascular permeability through the Wnt-canonical pathway involving WNT1-inducible signaling pathway protein 1 (WISPI). This study aimed to investigate the role of Frizzled-7 signaling in BBB preservation after ICH in mice.

Methods: Adult CD1 mice were subjected to sham surgery or collagenase-induced ICH. Frizzled-7 activation or knockdown was performed by administration of Clustered Regularly Interspaced Palindromic Repeats (CRISPR) by intracerebroventricular injection at 48 h before ICH induction. WISP1 activation or WISP1 knockdown was performed to evaluate the underlying signaling pathway. Post-ICH assessments included neurobehavior, brain edema, BBB permeability, hemoglobin level, western blot and immunofluorescence.

Results: The brain expressions of Frizzled-7 and WISP1 significantly increased post-ICH. Frizzled-7 was expressed in endothelial cells, astrocytes, and neurons after ICH. Activation of Frizzled-7 significantly improved neurological function, reduced brain water content and attenuated BBB permeability to large molecular weight substances after ICH. Whereas, knockdown of Frizzled-7 worsened neurological function and brain edema after ICH. Activation of Frizzled-7 significantly increased the expressions of Dvl, β-Catenin, WISP1, VE-Cadherin, Claudin-5, ZO-1 and reduced the expression of phospho-β-Catenin. WISP1 knockdown abolished the effects of Frizzled-7 activation on the expressions of VE-Cadherin, Claudin-5 and ZO-1 at 24 h after ICH.

Conclusions: Frizzled-7 activation potentially attenuated BBB permeability and improved neurological deficits after ICH through Dvl​​/β-Catenin/WISP1 pathway. Frizzled-7 may be a potential target for the development of ICH therapeutic drugs.

Keywords: Blood–brain barrier; Dvl; Frizzled-7; Intracerebral hemorrhage; WISP1; β-Catenin.

MeSH terms

  • Animals
  • Behavior, Animal
  • Blood-Brain Barrier* / metabolism
  • Blood-Brain Barrier* / physiopathology
  • CCN Intercellular Signaling Proteins / metabolism*
  • Cerebral Hemorrhage* / metabolism
  • Cerebral Hemorrhage* / physiopathology
  • Disease Models, Animal
  • Dishevelled Proteins / metabolism*
  • Frizzled Receptors / metabolism*
  • Male
  • Mice
  • Mice, Inbred CFTR
  • Proto-Oncogene Proteins / metabolism*
  • Signal Transduction / physiology
  • beta Catenin / metabolism*

Substances

  • CCN Intercellular Signaling Proteins
  • CCN4 protein, mouse
  • Dishevelled Proteins
  • Frizzled Receptors
  • Fzd7 protein, mouse
  • Proto-Oncogene Proteins
  • beta Catenin