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

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.

High-Throughput mRNA Sequencing Reveals Potential Therapeutic Targets of Febuxostat in Secondary Injury After Intracerebral Hemorrhage

“…The wnt signaling pathway is one of the most important signaling pathways which regulates cell proliferation, differentiation, apoptosis, stem cell self-renewal, tissue homeostasis, and wound healing. In the wnt signaling pathway, Wnt3a, β -catenin, and Frizzled-7 may be associated with cell apoptosis and proliferation and may change the BBB permeability in the ICH model ( Zhou et al, 2014 ; He et al, 2021 ). Accordingly, we determined the effects of febuxostat on the expression of Wisp1 and Wnt7b ( Figure 7 ).…”

Circular RNA PUM1 performs as a competing endogenous RNA of microRNA-340-5p to mediate DEAD-box helicase 5 to mitigate cerebral ischemia-reperfusion injury

“…BW was measured by the wet/dry method [ 21 ]. Briefly, the wet weight (WW) of brain specimens was calculated by an electronic analytical balance (APX-60, Denver Instrument, NY), while the dry weight (DW) was recorded after drying in an oven at 100°C for 72 h. BM = [(ww – dw)/ww] × 100%.…”

Activation of Wnt/Beta-Catenin Signaling Pathway as a Promising Therapeutic Candidate for Cerebral Ischemia/Reperfusion Injury

“…In an experimental intracerebral hemorrhage model in mice, activation of Wnt signaling by Frizzled-7 modified by CRISPR substantially reduced cerebral edema, BBB leakage, and associated behavioral deficiency, while downregulated expression of Frizzled-7 markedly aggravated the above phenomenon. Further, it was found that the activation of Frizzled-7-mediated Wnt/β-catenin signaling mostly takes place in the perihematomal endothelial cells, neurons, and astrocytes ( He et al, 2021 ). The potential implications of Wnt/β-catenin among cells from ischemic brain are depicted in Figure 3 .…”