bFGF ameliorates focal ischemic injury by blood flow-independent mechanisms in eNOS mutant mice.
Genetically engineered mice deficient in the expression of type III nitric oxide synthase (NOS) [endothelial NOS (eNOS)] were used to decipher the importance of nitric oxide (NO)-dependent augmentation of regional cerebral blood flow (rCBF) to infarct volume reduction following basic fibroblast growth factor (bFGF) infusion during acute middle cerebral artery (MCA) occlusion. We have shown previously that intravenously administered bFGF reduces infarct volume following MCA occlusion in rats and that bFGF dilates cerebral pial arterioles by NO-dependent mechanisms. Halothane-anesthetized eNOS knockout and wild-type mice were subjected to permanent MCA occlusion by intraluminal filament for 24 h. bFGF (100 microg x kg(-1) x h(-1)) was infused intravenously for 2 h, beginning 15 min after the onset of occlusion. Infarct volume was reduced from 119 +/- 8 to 93 +/- 4 mm3 (22% reduction, P < 0.05) or from 102 +/- 9 to 77 +/- 6 mm3 (24% reduction, P < 0.05) in eNOS knockout or wild-type mice, respectively (means +/- SE; n = 10 per group), and neurological deficits were also significantly reduced. Although bFGF infusion caused a 27% increase in rCBF and a 17% reduction in vascular resistance in the infarct margin of wild-type animals as measured by laser Doppler flowmetry, bFGF did not enhance rCBF in the infarct margin of eNOS mutant mice. These data indicate that intravenous bFGF reduces infarct volume following focal ischemia by mechanisms that are largely blood flow independent.
Huang
Z
Z
Laboratory of Stroke and Neurovascular Regulation, Massachusetts General Hospital and Harvard Medical School, Boston 02129, USA.
Chen
K
K
Huang
P L
PL
Finklestein
S P
SP
Moskowitz
M A
MA
D000818:Animals; D002544:Cerebral Infarction / Q000517:prevention & control* / Q000628:therapy; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000201:enzymology*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage / Q000494:pharmacology*; D007262:Infusions, Intravenous; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D051381:Rats; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects
D016222:Fibroblast Growth Factor 2; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase