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

Gab Seok Kim, Li Yang, Guoqi Zhang, Honggang Zhao, Magdy Selim, Louise D. McCullough, Michael J. Kluk and Teresa Sanchez ()
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Gab Seok Kim: the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School
Li Yang: the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School
Guoqi Zhang: the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School
Honggang Zhao: the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School
Magdy Selim: Beth Israel Deaconess Medical Center, Harvard Medical School
Louise D. McCullough: University of Connecticut School of Medicine
Michael J. Kluk: Brigham and Women’s Hospital, Harvard Medical School
Teresa Sanchez: the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8893

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