VEGF increases blood-brain barrier permeability to Evans blue dye and tetanus toxin fragment C but not adeno-associated virus in ALS mice.
Entry of most compounds into the CNS is impeded by the blood-brain barrier (BBB). Because vascular endothelial growth factor (VEGF) is important in the formation and maintenance of the BBB and is known to modulate BBB permeability in newborn rodents, we tested the hypothesis that VEGF may enhance BBB permeability in adult mice. We examined the effect of VEGF on the CNS distribution of three different agents: a small molecule (Evans blue dye) that is known to bind plasma proteins, an exogenous protein (tetanus toxin fragment C; TTC), and a viral vector (recombinant adeno-associated virus serotype 2/5 marked with lacZ; rAAV2/5-lacZ). Pretreatment with VEGF (20 mug; i.v.) increased permeability of the BBB to Evans blue dye and TTC as detected by augmented concentrations of these substances in the cerebrum, brainstem, and spinal cord. By contrast, VEGF did not alter BBB permeability to AAV2/5-lacZ, as defined by beta-galactosidase activity assay. These data demonstrate the potential utility of VEGF for pharmacological modulation of the BBB, and indicate that the increase in BBB permeability mediated by VEGF is limited by the size of the delivered substance.
Ay
Ilknur
I
Day Neuromuscular Research Laboratory, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. iay@partners.org
Francis
Jonathan W
JW
Brown
Robert H
RH
D000256:Adenoviridae / Q000502:physiology*; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000821:virology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000821:virology*; D002490:Central Nervous System / Q000378:metabolism; D004396:Coloring Agents / Q000493:pharmacokinetics*; D003627:Data Interpretation, Statistical; D004797:Enzyme-Linked Immunosorbent Assay; D005070:Evans Blue / Q000493:pharmacokinetics*; D005260:Female; D007763:Lac Operon; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D010446:Peptide Fragments / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013744:Tetanus Toxin / Q000493:pharmacokinetics*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D000519:alpha-Galactosidase / Q000378:metabolism
D004396:Coloring Agents; D010446:Peptide Fragments; D011994:Recombinant Proteins; D013744:Tetanus Toxin; D042461:Vascular Endothelial Growth Factor A; C040635:tetanus toxin fragment C; D005070:Evans Blue; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000519:alpha-Galactosidase