Vitamin D prevents hypoxia/reoxygenation-induced blood-brain barrier disruption via vitamin D receptor-mediated NF-kB signaling pathways

PLoS One. 2015 Mar 27;10(3):e0122821. doi: 10.1371/journal.pone.0122821. eCollection 2015.

Abstract

Maintaining blood-brain barrier integrity and minimizing neuronal injury are critical components of any therapeutic intervention following ischemic stroke. However, a low level of vitamin D hormone is a risk factor for many vascular diseases including stroke. The neuroprotective effects of 1,25(OH)2D3 (vitamin D) after ischemic stroke have been studied, but it is not known whether it prevents ischemic injury to brain endothelial cells, a key component of the neurovascular unit. We analyzed the effect of 1,25(OH)2D3 on brain endothelial cell barrier integrity and tight junction proteins after hypoxia/reoxygenation in a mouse brain endothelial cell culture model that closely mimics many of the features of the blood-brain barrier in vitro. Following hypoxic injury in bEnd.3 cells, 1,25(OH)2D3 treatment prevented the decrease in barrier function as measured by transendothelial electrical resistance and permeability of FITC-dextran (40 kDa), the decrease in the expression of the tight junction proteins zonula occludin-1, claudin-5, and occludin, the activation of NF-kB, and the increase in matrix metalloproteinase-9 expression. These responses were blocked when the interaction of 1,25(OH) )2D3 with the vitamin D receptor (VDR) was inhibited by pyridoxal 5'-phosphate treatment. Our findings show a direct, VDR-mediated, protective effect of 1,25(OH) )2D3 against ischemic injury-induced blood-brain barrier dysfunction in cerebral endothelial cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / drug effects
  • Brain Injuries
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / metabolism
  • Brain Ischemia / physiopathology
  • Cell Hypoxia / drug effects
  • Endothelial Cells / drug effects
  • Endothelial Cells / pathology
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / pathology
  • NF-kappa B / metabolism
  • Receptors, Calcitriol / metabolism*
  • Signal Transduction / drug effects
  • Stroke / drug therapy*
  • Stroke / metabolism
  • Stroke / physiopathology
  • Vitamin D / administration & dosage*

Substances

  • NF-kappa B
  • Receptors, Calcitriol
  • Vitamin D