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

BACKGROUND: 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.

METHODS: 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.

FINDINGS: 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).

INTERPRETATION: 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.