Hypertrophy of cerebral arterioles in mice deficient in expression of the gene for CuZn superoxide dismutase

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 mu m(2); ETH = 18 +/- 1 and 34 +/- 2%) compared with wild-type mice (CSA = 327 +/- 28 mu m(2); 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 mu m(2); ETH = 12 versus 28%). In addition, dilatation of cerebral arterioles in response to acetylcholine, but not nitroprusside, was reduced by approximate to 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 O2-, induction of cerebral vascular hypertrophy and impaired endotheliumdependent dilatation.