Abstract
BackgroundDestruction 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.MethodsAdult 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.ResultsThe 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.ConclusionsFrizzled-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.
Highlights
Intracerebral hemorrhage (ICH) is a life-threatening neurological disorder with high mortality [1, 2]
Of FZD7 expression was observed at 24 h (Fig. 2B), while that of WNT1-induciblesignaling pathway protein 1 (WISP1) was at 72 h post-intracerebral hemorrhage (ICH) (Fig. 2C)
Results of double immunofluorescence staining at 24 h post-ICH showed that FZD7 was co-localized with astrocytes, endothelial cells, and neurons at 24 h post-ICH, and it was mostly expressed in the area around the hematoma (Fig. 2D)
Summary
Intracerebral hemorrhage (ICH) is a life-threatening neurological disorder with high mortality (the 5-year mortality rate higher than 50%) [1, 2]. There is no proven effective medical or surgical treatments available for ICH patients, surgical decompression for He et al Fluids Barriers CNS (2021) 18:44 cerebellar hemorrhages is accepted as potentially lifesaving approach [1]. Tight junction proteins (TJPs), like claudins, occludin and junction adhesion molecule-1, span the membrane of two adjacent endothelial cells of the BBB, which forms a protective barrier between the brain and blood. The degradation of these transmembrane proteins reduces the barrier integrity and increases paracellular permeability thereby worsening brain edema [6, 7]. This study aimed to investigate the role of Frizzled-7 signaling in BBB preservation after ICH in mice
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