Published Online
on May 24, 2007

A more recent version of this article appeared on July 1, 2007

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Submitted on November 6, 2006
Revised on January 15, 2007
Accepted on February 1, 2007

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; and Christopher G. Sobey PhD^*

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

^* To whom correspondence should be addressed. 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 17-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 17-estradiol decreased superoxide production (P<0.05). NADPH-induced relaxations of BA were smaller in 17-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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