BFGF AMELIORATES FOCAL ISCHEMIC-INJURY BY BLOOD FLOW-INDEPENDENT MECHANISMS IN ENOS MUTANT MICE

Genetically engineered mice deficient in the expression of type III ni tric oxide synthase (NOS) [endothelial NOS (eNOS)] were used to deciph er the importance of nitric oxide (NO)-dependent augmentation of regio nal cerebral blood flow (rCBF) to infarct volume reduction following b asic fibroblast growth factor (bFGF) infusion during acute middle cere bral artery (MCA) occlusion. We have shown previously that intravenous ly administered bFGF reduces infarct volume following MCA occlusion in rats and that bFGF dilates cerebral pial arterioles by NO-dependent m echanisms. Halothane-anesthetized eNOS knockout and wild-type mice wer e subjected to permanent MCA occlusion by intraluminal filament for 24 h. bFGF (100 mu g . kg(-1). h(-1)) was infused intravenously for 2 h, beginning 15 min after the onset of occlusion. Infarct volume was red uced from 119 +/- 8 to 93 +/- 4 mm(3) (22% reduction, P < 0.05) or fro m 102 +/- 9 to 77 +/- 6 mm(3) (24% reduction, P < 0.05) in eNOS knocko ut or wild-type mice, respectively (means +/- SE; n = 10 per group), a nd neurological deficits were also significantly reduced. Although bFG F infusion caused a 27% increase in rCBF and a 17% reduction in vascul ar resistance in the infarct margin of wild-type animals as measured b y laser Doppler flowmetry, bFGF did not enhance rCBF in the infarct ma rgin of eNOS mutant mice. These data indicate that intravenous bFGF re duces infarct volume following focal ischemia by mechanisms that are l argely blood flow independent.