Published Online
on June 8, 2006

A more recent version of this article appeared on July 1, 2006

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Submitted on March 16, 2006
Accepted on April 6, 2006

Hypertrophy of Cerebral Arterioles in Mice Deficient in Expression of the Gene for CuZn Superoxide Dismutase

Gary L. Baumbach MD^*; Sean P. Didion PhD; and Frank M. Faraci PhD

From the Department of Pathology (G.L.B.), University of Iowa College of Medicine & Cardiovascular Center, Iowa City, IA; and the Department of Internal Medicine (S.P.D., F.M.F.), University of Iowa College of Medicine & Cardiovascular Center, Iowa City, IA.

^* To whom correspondence should be addressed. E-mail: g-baumbach{at}uiowa.edu.

Background and Purpose--Reactive oxygen species are believed to be an important determinant of vascular growth. We examined effects of genetic deficiency of copper-zinc superoxide dismutase (CuZnSOD; SOD1) on structure and function of cerebral arterioles.

Methods--Systemic arterial pressure (SAP) and cross-sectional area of the vessel wall (CSA) and superoxide (O_2^-) levels (relative fluorescence of ethidium [ETH]) were examined in maximally dilated cerebral arterioles in mice with targeted disruption of one (+/-) or both (-/-) genes encoding CuZnSOD. Wild-type littermates served as controls. Vasodilator responses were tested in separate groups of mice.

Results--CSA and ETH were significantly increased (P<0.05) in both CuZnSOD^+/- and CuZnSOD^-/- mice (CSA=435±24 and 541±48 µm²; ETH=18±1 and 34±2%) compared with wild-type mice (CSA=327±28 µm²; ETH=6%). Furthermore, the increases in CSA and ETH relative to wild-type mice were significantly greater (P<0.05) in CuZnSOD^-/- mice than in CuZnSOD^+/- mice (CSA=108 versus 214 µm²; ETH=12 versus 28%). In addition, dilatation of cerebral arterioles in response to acetylcholine, but not nitroprusside, was reduced by 25% in CuZnSOD^+/- (P<0.075) and 50% in CuZnSOD^-/- mice (P<0.05) compared with wild-type mice.

Conclusions--Cerebral arterioles in CuZnSOD^+/- and CuZnSOD^-/- mice undergo marked hypertrophy. These findings provide the first direct evidence in any blood vessel that CuZnSOD normally inhibits vascular hypertrophy suggesting that CuZnSOD plays a major role in regulation of cerebral vascular growth. The findings also suggest a gene dosing effect of CuZnSOD for increases in O_2^-, induction of cerebral vascular hypertrophy and impaired endothelium-dependent dilatation.

Key words: cerebral arteries • hypertrophy • reactive oxygen species • superoxide dismutase

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