Oestrogen receptors regulate vascular β₁- and β₃-adrenoceptor expression and shape sex-specific adrenergic control of vascular tone

Sex differences in vascular adrenergic responsiveness contribute to differential regulation of vascular tone. Female vessels exhibit enhanced β-adrenergic relaxation compared with males, but the role of oestrogen receptors in maintaining this phenotype and the capacity of sex hormone exposure to reprogram vascular β-adrenoceptor expression remain incompletely understood. Thoracic aorta and mesenteric arteries from Wistar Kyoto rats were examined following pharmacological oestrogen receptor inhibition or cross-sex hormone treatment. Vascular reactivity was assessed using wire myography, and β₁-, β₂-, and β₃-adrenoceptor mRNA expression was quantified by qPCR. Oestrogen receptor blockade with fulvestrant enhanced norepinephrine-induced vasoconstriction and reduced β-adrenergic relaxation in both conduit and resistance arteries. These functional alterations were accompanied by an approximately 50% reduction in β₁- and β₃-adrenoceptor mRNA expression, whereas β₂ expression remained unchanged. Conversely, oestrogen treatment in males attenuated vasoconstriction, enhanced β-adrenergic relaxation, and increased β₁- and β₃-adrenoceptor expression, while testosterone treatment in females had no effects. Despite pronounced vascular changes, arterial blood pressure remained unaltered. Analysis of human aorta, carotid, iliac, and mammary arteries revealed consistently higher β₁- and β₃-adrenoceptor mRNA expression in women compared with men. Oestrogen receptor inhibition reduces vascular β₁- and β₃-adrenoceptor expression and impairs β-adrenergic vasodilation, thereby shifting adrenergic vascular responses towards enhanced constriction. Conversely, oestrogen exposure reprogrammes the male vascular phenotype towards a female-like β-adrenergic profile. These findings identify an oestrogen receptor-dependent β₁/β₃-adrenoceptor axis as a conserved mechanism underlying sex-specific regulation of vascular tone.