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

Author

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  • Gab Seok Kim

    (the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School
    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
    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
    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
    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
    the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School
    Present address: Department of Pathology and Laboratory Medicine, Center for Vascular Biology, Weill Cornell Medical College, New York, New York 10065, USA)

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.

Suggested Citation

  • Gab Seok Kim & Li Yang & Guoqi Zhang & Honggang Zhao & Magdy Selim & Louise D. McCullough & Michael J. Kluk & Teresa Sanchez, 2015. "Critical role of sphingosine-1-phosphate receptor-2 in the disruption of cerebrovascular integrity in experimental stroke," Nature Communications, Nature, vol. 6(1), pages 1-15, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8893
    DOI: 10.1038/ncomms8893
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