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Junctional protein regulation by sphingosine kinase 2 contributes to blood-brain barrier protection in hypoxic preconditioning-induced cerebral ischemic tolerance.

Authors
  • Wacker, Bradley K
  • Freie, Angela B
  • Perfater, Jennifer L
  • Gidday, Jeffrey M
Type
Published Article
Journal
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
Publication Date
Jun 01, 2012
Volume
32
Issue
6
Pages
1014–1023
Identifiers
DOI: 10.1038/jcbfm.2012.3
PMID: 22314269
Source
Medline
License
Unknown

Abstract

Protection of the blood-brain barrier (BBB) is correlated with improved outcome in stroke. Sphingosine kinase (SphK)-directed production of sphingosine-1-phosphate, which we previously documented as being vital to preconditioning-induced stroke protection, mediates peripheral vascular integrity via junctional protein regulation. We used a hypoxic preconditioning (HPC) model in adult wild-type and SphK2-null mice to examine the isoform-specific role of SphK2 signaling for ischemic tolerance to transient middle cerebral artery occlusion and attendant BBB protection. Reductions in infarct volume and BBB permeability in HPC-treated mice were completely lost in SphK2-null mice. Hypoxic preconditioning-induced attenuation of postischemic BBB disruption in wild types, evidenced by reduced extravascular immunoglobulin G intensity, suggests direct protection of BBB integrity. Measurement of BBB junctional protein status in response to HPC revealed SphK2-dependent increases in triton-insoluble claudin-5 and VE-cadherin, which may serve to strengthen the BBB before stroke. Postischemic loss of VE-cadherin, occludin, and zona occludens-1 in SphK2-null mice with prior HPC suggests that SphK2-dependent protection of these adherens and tight junction proteins is compulsory for HPC to establish a vasculoprotective phenotype. Further elucidation of the mediators of this endogenous, HPC-activated lipid signaling pathway, and their role in protecting the ischemic BBB, may provide new therapeutic targets for cerebrovascular protection in stroke patients.

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