Junctional protein regulation by sphingosine kinase 2 contributes to blood-brain barrier protection in hypoxic preconditioning-induced cerebral ischemic tolerance.
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.
Department of Neurosurgery, Washington University School of Medicine, St Louis, Missouri, USA.
Bradley K
BK
Wacker
Angela B
AB
Freie
Jennifer L
JL
Perfater
Jeffrey M
JM
Gidday
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000201:enzymology*; D002545:Brain Ischemia / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D062507:Claudin-5; D057167:Claudins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019194:Ischemic Preconditioning; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D020521:Stroke / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D062826:Zonula Occludens-1 Protein; D000099157:Sphingosine Kinase; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D062507:Claudin-5; D057167:Claudins; D007527:Isoenzymes; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D062826:Zonula Occludens-1 Protein; D000099157:Sphingosine Kinase; D000099152:Cadherin 5; C491511:Cldn5 protein, mouse; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse