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Size-selective opening of the blood-brain barrier by targeting endothelial sphingosine 1-phosphate receptor 1.

TitleSize-selective opening of the blood-brain barrier by targeting endothelial sphingosine 1-phosphate receptor 1.
Publication TypeJournal Article
Year of Publication2017
AuthorsYanagida K, Liu CH, Faraco G, Galvani S, Smith HK, Burg N, Anrather J, Sanchez T, Iadecola C, Hla T
JournalProc Natl Acad Sci U S A
Volume114
Issue17
Pagination4531-4536
Date Published2017 Apr 25
ISSN1091-6490
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-specific S1pr1 knockout 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 of S1pr1iECKO mice showed altered subcellular distribution of tight junctional proteins. Pharmacological inhibition of S1P1 function led to transient BBB breach. These data suggest that brain endothelial S1P1 maintain the BBB by regulating the proper localization of tight junction proteins and raise the possibility that endothelial S1P1 inhibition may be a strategy for transient BBB opening and delivery of small molecules into the CNS.

DOI10.1073/pnas.1618659114
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID28396408
PubMed Central IDPMC5410849
Grant ListR01 NS037853 / NS / NINDS NIH HHS / United States
R01 NS100447 / NS / NINDS NIH HHS / United States
U54 HL117798 / HL / NHLBI NIH HHS / United States
R01 NS095441 / NS / NINDS NIH HHS / United States
R01 HL094465 / HL / NHLBI NIH HHS / United States
R37 NS089323 / NS / NINDS NIH HHS / United States
R01 HL089934 / HL / NHLBI NIH HHS / United States
R35 HL135821 / HL / NHLBI NIH HHS / United States