Sex-difference in expression and function of beta-adrenoceptors in macrovessels: role of the endothelium

Estrogen modulates adrenergic reactivity of macrovessels, resulting in weaker a-adrenergic vasoconstriction in females than males. However, the mechanisms governing this important sex-specific difference are not well understood. We hypothesized that vessels of females express more dilatory beta-adrenoceptors, which counteract constrictive effects of alpha-adrenoceptors. This hypothesis was tested using aortas of normotensive (WKY) and hypertensive rats (SHR), along with human mammary artery. Selective blockade of beta(1) (CGP20712) or beta(3) (SR59230A), but not beta(2) (ICI118,551) adrenoceptors, greatly increased alpha-adrenergic constriction (norepinephrine) of aorta in female SHRs, but not in male SHRs at 12 weeks of age. Consistently, the selective beta(1)/beta(2) (isoproterenol) and beta(3)-adrenergic (BRL37344) relaxation was stronger in female SHRs than in males. Removal of endothelium and use of L-NMMA abolished sex-difference in a-adrenergic constriction and beta-adrenergic relaxation. Immunostainings revealed endothelial localization of beta(1)- and beta(3)-adrenoceptors. mRNA levels of aortic beta(1)- and beta(3)-, but not beta(2)-adrenoceptors were markedly higher in female than in male SHRs. The sex-specific differences in alpha-adrenergic constriction and beta-adrenoceptor mRNA levels were age-dependent, predominantly present up to 29 weeks and disappeared at 36 weeks of age. The sex-specific difference was not strain-dependent and was similarly present in normotensive WKY rats. Human mammary artery of women showed a weaker alpha-adrenergic constriction than arteries of men. This sex-specific difference was prominent at 45-65 years and disappeared with aging. Our results convincingly demonstrate that female macrovessels express more dilatory beta(1)- and beta(3)-adrenoreceptors than male vessels with a predominant endothelial localization. This sex-specific difference is functionally relevant in young adults and is attenuated with aging.