Hypoxic preconditioning-induced cerebral ischemic tolerance: Role of microvascular sphingosine kinase 2

Bradley K. Wacker, Tae Sung Park, Jeffrey M. Gidday

Research output: Contribution to journalArticlepeer-review

93 Scopus citations


Background and Purpose-: The importance of bioactive lipid signaling under physiological and pathophysiological conditions is progressively becoming recognized. The disparate distribution of sphingosine kinase (SphK) isoform activity in normal and ischemic brain, particularly the large excess of SphK2 in cerebral microvascular endothelial cells, suggests potentially unique cell-and region-specific signaling by its product sphingosine-1-phosphate. The present study sought to test the isoform-specific role of SphK as a trigger of hypoxic preconditioning (HPC)-induced ischemic tolerance. Methods-: Temporal changes in microvascular SphK activity and expression were measured after HPC. The SphK inhibitor dimethylsphingosine or sphingosine analog FTY720 was administered to adult male Swiss-Webster ND4 mice before HPC. Two days later, mice underwent a 60-minute transient middle cerebral artery occlusion and at 24 hours of reperfusion, infarct volume, neurological deficit, and hemispheric edema were measured. Results-: HPC rapidly increased microvascular SphK2 protein expression (1.7±0.2-fold) and activity (2.5±0.6-fold), peaking at 2 hours, whereas SphK1 was unchanged. SphK inhibition during HPC abrogated reductions in infarct volume, neurological deficit, and ipsilateral edema in HPC-treated mice. FTY720 given 48 hours before stroke also promoted ischemic tolerance; when combined with HPC, even greater (and dimethylsphingosine-reversible) protection was noted. Conclusions-: These findings indicate hypoxia-sensitive increases in SphK2 activity may serve as a proximal trigger that ultimately leads to sphingosine-1-phosphate-mediated alterations in gene expression that promote the ischemia-tolerant phenotype. Thus, components of this bioactive lipid signaling pathway may be suitable therapeutic targets for protecting the neurovascular unit in stroke.

Original languageEnglish
Pages (from-to)3342-3348
Number of pages7
Issue number10
StatePublished - Oct 2009


  • Bioactive lipids
  • Endothelium
  • Focal stroke
  • Neuroprotection
  • Neurovascular unit


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