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-specific <i>S1pr1</i> knockout mice (<i>S1pr1</i>^<i>iECKO</i> ) 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 <i>S1pr1</i>^<i>iECKO</i> 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.