title: 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.
authors.affiliation: Department of Emergency Medicine, the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.|Department of Surgery, the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Gab Seok
authors.initials: GS
authors.lastname: Kim
authors.affiliation: Department of Emergency Medicine, the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.|Department of Surgery, the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Emergency Medicine, the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.|Department of Surgery, the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Guoqi
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Emergency Medicine, the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.|Department of Surgery, the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Honggang
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, RN-227A, Boston, Massachusetts 02215, USA.
authors.forename: Magdy
authors.initials: M
authors.lastname: Selim
authors.affiliation: Department of Neurology, University of Connecticut School of Medicine, Farmington, Connecticut 06030, USA.
authors.forename: Louise D
authors.initials: LD
authors.lastname: McCullough
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kluk
authors.affiliation: Department of Emergency Medicine, the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.|Department of Surgery, the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Sanchez
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D002199:Capillary Permeability; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000378:metabolism; D008875:Middle Aged; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011720:Pyrazoles; D011725:Pyridines; D011897:Random Allocation; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D000081025:Sphingosine-1-Phosphate Receptors; D055815:Young Adult
chemical_list: C471998:JTE 013; D011720:Pyrazoles; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; C477522:S1PR2 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C533955:sphingosine-1-phosphate receptor-2, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse