Chronic effects of VEGF adenovirus transfection into adult rat hippocampus

Vascular Endothelial Growth Factor (VEGF) is a cytokine growth factor that regulates vasculogenesis and angiogenesis. In addition to its vascular effects, VEGF has more recently been associated with nonvascular effects. We sought to study the effects of continuous expression of VEGF induced via adenoviral vector (AdVEGF) in the rat hippocampus. When brains were examined four weeks following AdVEGF administration, the hippocampi were severely damaged and the lateral ventricles were dramatically enlarged. Neither control adenovirus expression nor VEGF expression induced via adeno-associated viral vector led to degeneration. We sought to characterize and learn about the mechanism of this AdVEGF-induced degeneration. Administration of a control adenovirus followed by infusion of exogenous VEGF protein for four weeks did not lead to hippocampal atrophy or ventricular enlargement, suggesting that the degenerative effect relied on expression of VEGF via adenovirus. Time-course experiments showed that the degeneration takes place largely between seven and twelve days after AdVEGF administration. Adenoviral administration of the anti-leak protein Angiopoietin-1 with VEGF adenovirus did not prevent AdVEGF-induced degeneration, indicating that the degeneration was not due to vascular leak. Infusion of the corticosteroid anti-inflammatory Dexamethasone for four weeks following AdVEGF administration did not prevent degeneration, indicating that AdVEGF's effects were not due to inflammation. To explore the receptor specificity of AdVEGF-induced degeneration, we induced expression of Placental Growth Factor, a VEGF family member which binds only to VEGFR-1 and NP-1, via adenoviral vector (AdPlGF). Four weeks after adenoviral administration, AdPlGF-treated brains did not show hippocampal degeneration or ventricular enlargement, suggesting that AdVEGF-induced degeneration is VEGFR-2-mediated. We hypothesize that the rapid increase in VEGF expression induced by AdVEGF---and the pattern of VEGF binding that follows---results in a downregulation or dysregulation of VEGFR-2, leading to hippocampal degeneration.