Vascular Endothelial Growth Factors Enhance the Permeability of the Mouse Blood-brain Barrier

Shize Jiang,Yong Jiang,Lei Wang,Rui Xia,Fabao Gao,Robyn Klein

doi:10.1371/journal.pone.0086407

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.

Highlights

The blood-brain barrier (BBB) is a dynamically regulated physical barrier between the central nervous system (CNS) and circulation consisting of endothelial cells (ECs) that line cerebral microvessels [1,2]
In order to define the time window of enhanced BBB permeability after vascular endothelial growth factor (VEGF) injections, we varied the delay between VEGF injection and administration of the contrast agent Gd-DTPA from 0.5 to 12 h (Figure 1)
To determine the concentration inducing the largest permeability increase without brain edema, mice were treated with saline, 1.6 mg VEGF or 3 mg VEGF and BBB permeability and edema assessed 828.5 h later by magnetic resonance imaging (MRI) and histology

Summary

Introduction

The blood-brain barrier (BBB) is a dynamically regulated physical barrier between the CNS and circulation consisting of endothelial cells (ECs) that line cerebral microvessels [1,2]. While the BBB sustains the unique chemical microenvironment critical for neuronal activity in the CNS, it restricts access to therapeutic drugs. These ECs are distinct from peripheral ECs in that they have a continuous basement membrane with no fenestrae and low pinocytotic activity [2]. It has been estimated that almost all large-molecule drugs and more than 98% of small molecule drugs cannot cross the BBB. Only small lipid-soluble molecules demonstrate significant BBB permeability [3,4,5]

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