Effects of intraventricular infusion of vascular endothelial growth factor on cerebral blood flow, edema, and infarct volume.

Abstract

Therapeutic cerebral angiogenesis, utilizing angiogenic factors to enhance collateral vessel formation within the central nervous system, is a potential method for cerebral revascularization. A prior dose-response study determined that intracerebroventricular infusion of vascular endothelial growth factor (VEGF) increases vascular density with minimal associated brain edema at a concentration of 5 microg/ml. The purpose of this study was to assess effects of intracerebroventricular infusion of VEGF (5 microg/ml) on cerebral blood flow, infarct volume, and brain edema after ischemia. Recombinant human VEGF(165) was infused into the right lateral ventricle of rats with an osmotic minipump at a rate of 1 microl/hr for 7 days. Control animals received vehicle only. Ischemia was produced by transient (2 hours) middle cerebral artery occlusion (MCAO). After MCAO, cerebral blood flow was determined with the indicator fractionation technique: infarct volume was assessed with 2,3,5-triphenlytetrazolium chloride staining, and brain edema was determined by measuring brain water content. Cerebral blood flow was not significantly different in animals treated with VEGF compared to controls. There was a significant reduction in total infarct volume after temporary MCAO in VEGF-treated animals compared to controls (163+/-37 mm(3) vs. 309+/-54 mm(3), P<0.05). Brain water content after transient MCAO was also significantly reduced in VEGF-treated animals compared to controls (80.9+/-0.7% vs. 83.3+/-0.6%, P<0.05). Intracerebroventricular infusion of VEGF(165) (5 microg/ml) decreases infarct volume and brain edema after temporary MCAO without a significant increase in cerebral blood flow. These results indicate that VEGF may have a direct neuroprotective effect in cerebral ischemia.