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(Stroke. 2007;38:2142.)
© 2007 American Heart Association, Inc.

Original Contributions

Effect of Gender on NADPH-Oxidase Activity, Expression, and Function in the Cerebral Circulation

Role of Estrogen

Alyson A. Miller, PhD; Grant R. Drummond, PhD; Anja E. Mast, BSc; Harald H.H.W. Schmidt, PhD Christopher G. Sobey, PhD

From the Department of Pharmacology and Centre for Vascular Health, Monash University, Clayton, Melbourne, Victoria, Australia.

Correspondence to Christopher G. Sobey, PhD, Associate Professor, Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia. E-mail chris.sobey{at}med.monash.edu.au

Background and Purpose— This study tested whether NADPH-oxidase activity, expression, and functional effects on vascular tone are influenced by gender in the rat cerebral circulation and whether such differences are estrogen-dependent.

Methods— NADPH-stimulated superoxide production by cerebral (basilar [BA]; middle cerebral) arteries from male and female Sprague-Dawley rats was measured using lucigenin-enhanced chemiluminescence and dihydroethidium. Protein expression of Nox1, Nox2, Nox4, superoxide dismutase 1 (SOD1), SOD2, and SOD3 was measured using Western blotting. Vascular responses of BA to NADPH were assessed in a myograph. Some female rats were ovariectomized and treated with either vehicle (dimethyl sulfoxide) or 17ß-estradiol.

Results— NADPH-stimulated superoxide production by BA and middle cerebral arteries from males was approximately 2-fold greater than vessels from females. Superoxide production was virtually abolished by the NADPH-oxidase inhibitor, diphenyleneiodonium. Protein expression of Nox1 and Nox4 in BA was also higher in males than in females (2.4- and 2.8-fold, respectively), whereas Nox2, SOD1, SOD2, and SOD3 expression did not differ between genders. NADPH induced greater vasorelaxant effects in BA from males versus females (P<0.05). The hydrogen peroxide scavenger, catalase, abolished these NADPH-induced relaxations. NADPH-stimulated superoxide production by BA from ovariectomized rats treated with vehicle was 3-fold greater than levels in intact females. Treatment of ovariectomized rats with 17ß-estradiol decreased superoxide production (P<0.05). NADPH-induced relaxations of BA were smaller in 17ß-estradiol-treated than in vehicle-treated ovariectomized rats (P<0.05).

Conclusions— NADPH-oxidase activity and function are lower in cerebral arteries of female rats. These gender differences are estrogen-dependent and are associated with lower Nox1 and Nox4 expression.

Key Words: cerebral arteries • gender • NADPH oxidase • reactive oxygen species

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