Normalization of non‐canonical Wnt signalings does not compromise blood‐brain barrier protection conferred by upregulating endothelial Wnt/β‐catenin signaling following ischemic stroke

Abstract

Background Endothelial canonical (Wnt/β‐catenin) and non‐canonical Wnt signalings (Wnt/PCP and Wnt/Ca2+) promote blood‐brain barrier (BBB) development and antagonize each other. However, the effects of ischemic stroke on endothelial canonical and non‐canonical Wnt signalings are unclear. Further, how non‐canonical Wnt signalings are influenced by upregulation of endothelial Wnt/β‐catenin signaling and subsequently affect BBB function following ischemic stroke have not been studied. Methods First, we determined the levels of Wnt signaling markers including TCF/LEF1 transcription activity, Axin2 mRNA, phospho‐JNKThr183/Tyr185, and NFAT in brain endothelial cells (ECs) with the deletion of Wnt receptor Frizzled (Fzd)4 or Fzd6, the two most abundant Fzds in brain ECs. Next, we observed the effect of ischemia/reperfusion injury on Wnt signalings in brain ECs and adult mice. Last, we assessed the changes of non‐canonical Wnt signalings and BBB injury in the early stage of ischemic stroke in mice with endothelial β‐catenin activation (β‐cat mice). Results Fzd4 or Fzd6 deletion dampened both Wnt/β‐catenin and Wnt/PCP signalings but enhanced Wnt/Ca2+ signaling in brain ECs. Both canonical and non‐canonical Wnt signalings in brain ECs were downregulated after ischemia/reperfusion injury in vitro and in vivo. Upregulating endothelial Wnt/β‐catenin signaling in β‐cat mice normalized the downregulated non‐canonical Wnt signalings, which did not compromise its protective effects on BBB integrity and endothelial tight junction following ischemic stroke. Conclusions The BBB protection induced by upregulation of endothelial Wnt/β‐catenin signaling may be not interfered by the normalization of non‐canonical Wnt signalings in the early stage of ischemic stroke.

Lithium attenuates blood–brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/β‐catenin signaling‐dependent mechanism in mice

“…The canonical Wnt/β-catenin signaling pathway is a key regulator of the BBB and is critical for the stabilization of brain endothelial tight junctions. [39][40][41] Lithium, the first GSK-3β inhibitor, increases the phosphorylation of GSK-3β at Ser9 in vivo and upregulates Wnt/βcatenin signaling. 42 Although a previous study reported the effect of lithium on BBB damage in experimental ICH, the mechanism was not clarified.…”

“…The canonical Wnt/β‐catenin signaling pathway is a key regulator of the BBB and is critical for the stabilization of brain endothelial tight junctions 39–41 . Lithium, the first GSK‐3β inhibitor, increases the phosphorylation of GSK‐3β at Ser9 in vivo and upregulates Wnt/β‐catenin signaling 42 .…”

Advancing stroke therapy: A deep dive into early phase of ischemic stroke and recanalization

“…66 Interestingly, normalization of non-canonical Wnt signaling does not compromise BBB protection conferred by upregulating endothelial Wnt/β-catenin signaling following ischemic stroke. 67 This suggests that a balance between canonical and noncanonical Wnt signaling pathways may be crucial for maintaining BBB integrity. pathway could significantly influence outcomes following ischemic stroke.…”

CD31 as a probable responding and gate-keeping protein of the blood-brain barrier and the risk of Alzheimer’s disease

“…Recent studies further support endothelial cells and associated Wnt/β-catenin signaling involved in barrier maintenance and transporter regulation. 3–5 BBB breakdown facilitates entry of neurotoxic blood-derived products into the brain, enhancing the neuroinflammatory response 6 and AD pathogenesis. 7,8…”

“…Recent studies further support endothelial cells and associated Wnt/b-catenin signaling involved in barrier maintenance and transporter regulation. [3][4][5] BBB breakdown facilitates entry of neurotoxic blood-derived products into the brain, enhancing the neuroinflammatory response 6 and AD pathogenesis. 7,8 During peripheral chronic inflammation, some circulating inflammatory factors, such as C-reactive protein (CRP), have the potential to act on the blood-facing endothelia in the brain, facilitating or causing AD pathology.…”