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

TitleCritical role of sphingosine-1-phosphate receptor-2 in the disruption of cerebrovascular integrity in experimental stroke.
Publication TypeJournal Article
Year of Publication2015
AuthorsKim GSeok, Yang L, Zhang G, Zhao H, Selim M, McCullough LD, Kluk MJ, Sanchez T
JournalNat Commun
Date Published2015 Aug 05
KeywordsAdult, Aged, Animals, Brain, Capillary Permeability, Cells, Cultured, Cerebrovascular Circulation, Disease Models, Animal, Endothelial Cells, Endothelium, Vascular, Female, Humans, Infarction, Middle Cerebral Artery, Male, Matrix Metalloproteinase 9, Mice, Inbred C57BL, Mice, Knockout, Microvessels, Middle Aged, Neuroglia, Neurons, Pyrazoles, Pyridines, Random Allocation, Receptors, Lysosphingolipid, Sphingosine-1-Phosphate Receptors, Young Adult

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.

Alternate JournalNat Commun
PubMed ID26243335
PubMed Central IDPMC4587559
Grant ListR01 HL094465 / HL / NHLBI NIH HHS / United States
HL094465 / HL / NHLBI NIH HHS / United States
Related Faculty: 
Michael Kluk, M.D., Ph.D. Teresa Sanchez, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
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