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

Estrogen modulates adrenergic reactivity of macrovessels, resulting in weaker α-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 β-adrenoceptors, which counteract constrictive effects of α-adrenoceptors. This hypothesis was tested using aortas of normotensive (WKY) and hypertensive rats (SHR), along with human mammary artery. Selective blockade of β (CGP20712) or β (SR59230A), but not β (ICI118,551) adrenoceptors, greatly increased α-adrenergic constriction (norepinephrine) of aorta in female SHRs, but not in male SHRs at 12 weeks of age. Consistently, the selective β/β (isoproterenol) and β-adrenergic (BRL37344) relaxation was stronger in female SHRs than in males. Removal of endothelium and use of L-NMMA abolished sex-difference in α-adrenergic constriction and β-adrenergic relaxation. Immunostainings revealed endothelial localization of β- and β-adrenoceptors. mRNA levels of aortic β- and β-, but not β-adrenoceptors were markedly higher in female than in male SHRs. The sex-specific differences in α-adrenergic constriction and β-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 α-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 β- and β-adrenoreceptors than male vessels with a predominant endothelial localization. This sex-specific difference is functionally relevant in young adults and is attenuated with aging.