Cell-specific Blood-Brain Barrier Regulation in Health and Disease: A Focus on Hypoxia

Br J Pharmacol. 2014 Mar;171(5):1210-30. doi: 10.1111/bph.12489.

Abstract

The blood-brain barrier (BBB) is a complex vascular structure consisting of microvascular endothelial cells that line the vessel wall, astrocyte end-feet, pericytes, as well as the basal lamina. BBB cells act in concert to maintain the characteristic impermeable and low paracellular flux of the brain vascular network, thus ensuring a homeostatic neuronal environment. Alterations in BBB stability that occur during injury have dire consequences on disease progression and it is clear that BBB cell-specific responses, positive or negative, must make a significant contribution to injury outcome. Reduced oxygenation, or hypoxia, is a characteristic of many brain diseases that significantly increases barrier permeability. Recent data suggest that hypoxia-inducible factor (HIF-1), the master regulator of the hypoxic response, probably mediates many hypoxic effects either directly or indirectly via its target genes. This review discusses current knowledge of physiological cell-specific regulation of barrier function, their responses to hypoxia as well as consequences of hypoxic- and HIF-1-mediated mechanisms on barrier integrity during select brain diseases. In the final sections, the potential of current advances in targeting HIF-1 as a therapeutic strategy will be overviewed.

Keywords: BBB cell-specific response; HIF-1; astrocytes; endothelial cells; hypoxia; neurodegenerative diseases; pericytes.

Publication types

  • Review

MeSH terms

  • Animals
  • Astrocytes / metabolism
  • Blood-Brain Barrier / cytology
  • Blood-Brain Barrier / metabolism*
  • Endothelial Cells / metabolism
  • Humans
  • Hypoxia / metabolism*
  • Hypoxia-Inducible Factor 1 / metabolism*
  • Pericytes / metabolism

Substances

  • Hypoxia-Inducible Factor 1