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.


RESULTS
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).


CONCLUSIONS
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.
Harrigan
M R
MR
Department of Neurosurgery, University of Michigan Health System, Ann Arbor 48109, USA.
Ennis
S R
SR
Sullivan
S E
SE
Keep
R F
RF
D000818:Animals; D001929:Brain Edema / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*; D020520:Brain Infarction / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D007263:Infusions, Parenteral; D007276:Injections, Intraventricular; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D008222:Lymphokines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors