Vascular endothelial growth factor (VEGF) modulates vascular permeability and inflammation in rat brain

Vascular endothelial growth factor (VEGF) is an angiogenic growth factor th at also induces vascular permeability and macrophage migration. VEGF expres sion is weak in normal adult brain, but is strongly upregulated in glioma c ells and reactive astrocytes, suggesting that chronic overexpression of VEG F in the brain contributes to blood-brain barrier (BBB) breakdown. We exami ned the effects of chronic VEGF overexposure on the integrity of the BBB us ing the following approaches: 1) continuous intracerebral infusion of VEGF via miniosmotic pump; and 2) intracerebral injection of an adenoviral vecto r encoding the VEGF(165) gene (AdCMV.VEGF). After 6 days both treatments pr oduced similar to 10-fold breakdown of the BBB las measured by transport of C-14-aminoisobutyric acid (AIB) from blood into brain) compared with the r espective controls (albumin infusion or AdCMV.beta gal virus). BBB disrupti on in AdCMV.VEGF-treated brains was accompanied by a severe inflammatory re sponse not observed in brains receiving AdCMV.beta gal or VEGF protein infu sion, indicating that neither VEGF nor viral particles alone were responsib le for the inflammatory response. However, injection of AdCMV.beta gal foll owed by VEGF infusion to the same site also elicited inflammation. Chronic overexposure of normal brain to VEGF also increased intercellular adhesion molecule-1 (ICAM-1) and major histocompatibility complex (MHC) class I and II expression. Although VEGF itself is not inflammatory, VEGF may modulate immune responses in the central nervous system (CNS) by opening the BBB, al tering the immunoprivileged status of the brain, and allowing contact betwe en normally sequestered CNS antigens and blood-borne immune mediators.