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Critical role of sphingosine-1-phosphate receptor-2 in the disruption of cerebrovascular integrity in experimental stroke.

Abstract
The use and effectiveness of current stroke reperfusion therapies are limited by the complications of reperfusion injury, which include increased cerebrovascular permeability and haemorrhagic transformation. Sphingosine-1-phosphate (S1P) is emerging as a potent modulator of vascular integrity via its receptors (S1PR). By using genetic approaches and a S1PR2 antagonist (JTE013), here we show that S1PR2 plays a critical role in the induction of cerebrovascular permeability, development of intracerebral haemorrhage and neurovascular injury in experimental stroke. In addition, inhibition of S1PR2 results in decreased matrix metalloproteinase (MMP)-9 activity in vivo and lower gelatinase activity in cerebral microvessels. S1PR2 immunopositivity is detected only in the ischemic microvessels of wild-type mice and in the cerebrovascular endothelium of human brain autopsy samples. In vitro, S1PR2 potently regulates the responses of the brain endothelium to ischaemic and inflammatory injury. Therapeutic targeting of this novel pathway could have important translational relevance to stroke patients.
AuthorsGab Seok Kim, Li Yang, Guoqi Zhang, Honggang Zhao, Magdy Selim, Louise D McCullough, Michael J Kluk, Teresa Sanchez
JournalNature communications (Nat Commun) Vol. 6 Pg. 7893 (Aug 05 2015) ISSN: 2041-1723 [Electronic] England
PMID26243335 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • JTE 013
  • Pyrazoles
  • Pyridines
  • Receptors, Lysosphingolipid
  • S1PR2 protein, human
  • Sphingosine-1-Phosphate Receptors
  • sphingosine-1-phosphate receptor-2, mouse
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse
Topics
  • Adult
  • Aged
  • Animals
  • Brain (metabolism, physiopathology)
  • Capillary Permeability
  • Cells, Cultured
  • Cerebrovascular Circulation
  • Disease Models, Animal
  • Endothelial Cells (physiology)
  • Endothelium, Vascular (metabolism, physiopathology)
  • Female
  • Humans
  • Infarction, Middle Cerebral Artery (metabolism, physiopathology)
  • Male
  • Matrix Metalloproteinase 9 (metabolism)
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microvessels (metabolism)
  • Middle Aged
  • Neuroglia (metabolism)
  • Neurons (metabolism)
  • Pyrazoles
  • Pyridines
  • Random Allocation
  • Receptors, Lysosphingolipid (metabolism)
  • Sphingosine-1-Phosphate Receptors
  • Young Adult

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