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

Summary.

 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 μg/ml. The purpose of this study was to assess effects of intracerebroventricular infusion of VEGF (5 μg/ml) on cerebral blood flow, infarct volume, and brain edema after ischemia.

 Methods: Recombinant human VEGF₁₆₅ was infused into the right lateral ventricle of rats with an osmotic minipump at a rate of 1 μl/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 mm³ vs. 309±54 mm³, 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 VEGF₁₆₅ (5 μg/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.