title: Size-selective opening of the blood-brain barrier by targeting endothelial sphingosine 1-phosphate receptor 1.
abstract: The vasculature of the central nervous system (CNS) forms a selective barrier termed the blood-brain barrier (BBB). Disruption of the BBB may contribute to various CNS diseases. Conversely, the intact BBB restricts efficient penetration of CNS-targeted drugs. Here, we report the BBB-regulatory role of endothelial sphingosine 1-phosphate (S1P) receptor-1, a G protein-coupled receptor known to promote the barrier function in peripheral vessels. Endothelial-specificS1pr1knockout mice (S1pr1iECKO) showed BBB breach for small-molecular-mass fluorescence tracers (<3 kDa), but not larger tracers (>10 kDa). Chronic BBB leakiness was associated with cognitive impairment, as assessed by the novel object recognition test, but not signs of brain inflammation. Brain microvessels ofS1pr1iECKOmice showed altered subcellular distribution of tight junctional proteins. Pharmacological inhibition of S1P1function led to transient BBB breach. These data suggest that brain endothelial S1P1maintain the BBB by regulating the proper localization of tight junction proteins and raise the possibility that endothelial S1P1inhibition may be a strategy for transient BBB opening and delivery of small molecules into the CNS.
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA 20115.|Department of Surgery, Harvard Medical School, Boston, MA 20115.|Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yanagida
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Liu
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Faraco
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA 20115.|Department of Surgery, Harvard Medical School, Boston, MA 20115.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Galvani
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065.
authors.forename: Helen K
authors.initials: HK
authors.lastname: Smith
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Burg
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065.
authors.forename: Josef
authors.initials: J
authors.lastname: Anrather
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065.
authors.forename: Teresa
authors.initials: T
authors.lastname: Sanchez
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065.
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA 20115; timothy.hla@childrens.harvard.edu.|Department of Surgery, Harvard Medical School, Boston, MA 20115.|Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000098:blood supply; D042783:Endothelial Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology*; D005786:Gene Expression Regulation; D008246:Lysophospholipids; D051379:Mice; D018345:Mice, Knockout; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives; D019108:Tight Junctions / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D013110:Sphingosine
keywords: blood–brain barrier; drug delivery; endothelium; sphingosine 1–phosphate; tight junction