Size-selective opening of the blood-brain barrier by targeting endothelial sphingosine 1-phosphate receptor 1 Academic Article uri icon

Overview

MeSH Major

  • Angiotensin II
  • Calcium Signaling
  • Cyclooxygenase 1
  • Dinoprostone
  • Hypertension
  • Membrane Proteins
  • Neurons
  • Reactive Oxygen Species
  • Receptors, Prostaglandin E, EP1 Subtype
  • Subfornical Organ

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 (S1pr1(iECKO) ) 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 S1pr1(iECKO) 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.

publication date

  • April 25, 2017

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5410849

Digital Object Identifier (DOI)

  • 10.1073/pnas.1618659114

PubMed ID

  • 28396408

Additional Document Info

start page

  • 4531

end page

  • 4536

volume

  • 114

number

  • 17