Vascular endothelial growth factors enhance the permeability of the mouse blood-brain barrier

PLoS One. 2014 Feb 14;9(2):e86407. doi: 10.1371/journal.pone.0086407. eCollection 2014.

Abstract

The blood-brain barrier (BBB) impedes entry of many drugs into the brain, limiting clinical efficacy. A safe and efficient method for reversibly increasing BBB permeability would greatly facilitate central nervous system (CNS) drug delivery and expand the range of possible therapeutics to include water soluble compounds, proteins, nucleotides, and other large molecules. We examined the effect of vascular endothelial growth factor (VEGF) on BBB permeability in Kunming (KM) mice. Human VEGF165 was administered to treatment groups at two concentrations (1.6 or 3.0 µg/mouse), while controls received equal-volume saline. Changes in BBB permeability were measured by parenchymal accumulation of the contrast agent Gd-DTPA as assessed by 7 T magnetic resonance imaging (MRI). Mice were then injected with Evans blue, sacrificed 0.5 h later, and perfused transcardially. Brains were removed, fixed, and sectioned for histological study. Both VEGF groups exhibited a significantly greater signal intensity from the cerebral cortex and basal ganglia than controls (P<0.001). Evans blue fluorescence intensity was higher in the parenchyma and lower in the cerebrovasculature of VEGF-treated animals compared to controls. No significant brain edema was observed by diffusion weighted MRI (DWI) or histological staining. Exogenous application of VEGF can increase the permeability of the BBB without causing brain edema. Pretreatment with VEGF may be a feasible method to facilitate drug delivery into the CNS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Vessels / drug effects
  • Blood Vessels / pathology
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / pathology
  • Brain Edema / pathology
  • Evans Blue
  • Humans
  • Magnetic Resonance Imaging
  • Mice
  • Permeability / drug effects
  • Staining and Labeling
  • Vascular Endothelial Growth Factor A / pharmacology*

Substances

  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Evans Blue

Grant support

This work was supported by the National Natural Science Foundation of China (81130027 ; 81071204) (http://www.nsfc.gov.cn/),and the National Basic Research Program of China (973 Program, 2011CB935800) (http://www.973.gov.cn/English/Index.aspx). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.