Intraventricular infusion of vascular endothelial growth factor promotes cerebral angiogenesis with minimal brain edema

OBJECTIVE: Therapeutic cerebral angiogenesis, i.e., using angiogenic factors to enhance collateral vessel formation within the central nervous system, is a potential method for cerebral revascularization. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen that also increases capillary permeability, particularly in ischemic tissue. The purpose of this study was to assess the angiogenic and capillary permeability effects of chronic intraventricular infusion of exogenous VEGF in nonischemic brain tissue, because many patients with impaired cerebrovascular reserve do not exhibit chronic cerebral ischemia. METHODS: Recombinant human VEGF(165) was infused into the right lateral ventricle of rats at a rate of 1 mul/h for 7 days, at concentrations of 1 to 25 mug/ml, with osmotic minipumps. Control animals received vehicle only. Vessels were identified in laminin immunohistochemical analyses. Capillary permeability and brain edema were assessed with Evans blue extravasation, [H-3]inulin permeability, and brain water content measurements. RESULTS: Vessel density was dose-dependently increased by VEGF,65 infusions, with significant increases occurring in animals treated with 5 or 25 mug/ml, compared with control animals (P < 0.01). Significant enlargement of the lateral ventricles was observed for the highest-dose group but not for animals treated with other doses. Capillary permeability was assessed in animals treated with a dose of 5 μg/ml. An increase in capillary permeability in the diencephalon was identified with Evans blue extravasation and [H-3]inulin permeability assessments; however, the brain water content was not significantly increased. CONCLUSION: Chronic intraventricular infusions of VEGF165 increased vascular density in a dose-dependent manner. There seems to be a therapeutic window, because infusion of VEGF(165) at a concentration of 5 μg/ml resulted in a significant increase in vessel density with minimal associated brain edema and no ventriculomegaly.