Estrogen determines sex differences in adrenergic vessel tone by regulation of endothelial β-adrenoceptor expression

Abstract

Vessels of female rats constrict less and relax more to adrenergic stimulation than vessels of males. Although we have reported that these sex-specific differences rely on endothelial β-adrenoceptors, the role of sex hormones in β-adrenoceptor expression and related vessel tone regulation is unknown. We investigated the role of estrogen, progesterone and testosterone on β-adrenoceptor expression and adrenergic vessel tone regulation, along with sex-specific differences in human mammary arteries. The sex-specific differences in vasoconstriction and vasorelaxation in rat vessels were eliminated after ovariectomy in females. Ovariectomy increased vessel vasoconstriction to norepinephrine more than twofold. Vasorelaxations by isoprenaline and a β3-agonist were reduced after ovariectomy. Estrogen, but not progesterone substitution, restored sex-specific differences in vasoconstriction and vasorelaxation. Vascular mRNA levels of β1- and β3- but not β2-adrenoreceptors were higher in vessels of females compared with males. Ovariectomy reduced these differences by decreasing β1- and β3- but not β2-adrenoreceptor expression in females. Consistently, estrogen substitution restored β1- and β3-adrenoreceptor expression. Orchiectomy or testosterone treatment affected neither vasoconstriction and vasorelaxation nor β-adrenoceptor expression in vessels of male rats. In human mammary arteries, sex-specific differences in vasoconstriction and vasorelaxation were reduced after removal of endothelium or treatment with l-NMMA. Vessels of women showed higher levels of β1- and β3-adrenoceptors than in men. In conclusion, the sex-specific differences in vasoconstriction and vasorelaxation are common for rat and human vessels. In rats, these differences are estrogen but not testosterone or progesterone dependent. Estrogen determines these differences via regulation of vascular endothelial β1- and β3-adrenoreceptor expression. NEW & NOTEWORTHY This study proposes a mechanistic concept regulating sex-specific differences in adrenergic vasoconstriction and vasorelaxation. Estrogen increases vascular β1- and β3-adrenoceptor expression in female rats. This and our previous studies demonstrate that these receptors are located primarily on endothelium and when activated by norepinephrine act via nitric oxide (NO). Therefore, β-adrenergic stimulation leads to a more pronounced vasorelaxation in females. Coactivation of endothelial β1- and β3-adrenoreceptors leads to higher NO release in vessels of females, ultimately blunting vasoconstriction triggered by activation of smooth muscle α-adrenoceptors.

Acute intermittent hypercapnic hypoxia and sympathetic neurovascular transduction in men

“…) and have greater beta‐adrenergic sensitivity as a result of oestrogen‐dependent increases in beta‐adrenoceptor expression (Riedel et al . ).…”

“…Participants underwent a single night of sleep with nocturnal pulse oximetry (WristOx2, Model 3150; Nonin, Plymouth, MN, USA) and were excluded if they had indications of undiagnosed sleep apnoea, defined as an oxygen desaturation index ࣙ5 events h -1 (based on a desaturation ࣙ 4%; nVision, version 6.4; Nonin). Finally, only male participants were enrolled because women have a lower probability of developing OSA (Peppard et al 2013), are less sensitive to alpha-adrenergic stimulation (both alpha 1 and 2) (Schmitt et al 2010) and have greater beta-adrenergic sensitivity as a result of oestrogen-dependent increases in beta-adrenoceptor expression (Riedel et al 2019).…”

Effect of β1/β2‐adrenoceptor blockade on β3‐adrenoceptor activity in the rat cremaster muscle artery

“…Symbols represent mean ± SEM for n of 6 in each experimental group. Asterisk (*) indicates a significant effect of PKI on responses; Δ indicates a significant effect of nadolol on responses in the presence of PKI (P < .05, two-way ANOVA with Sidak's post hoc comparison) et al, 2001), although reported pEC 50 values for arterial relaxation are around 5 (Brawley et al, 2000;Flacco et al, 2013;Riedel et al, 2019).…”

Ageing augments β‐adrenergic cutaneous vasodilatation differently in men and women, with no effect on β‐adrenergic sweating

“…We do not know why the effect of ageing differs between men and women, but some insights can be gleaned from prior work. Examination of rat mesenteric arteries and human mammary arteries indicated that oestrogen augments β‐adrenergic endothelial receptor expression in females, resulting in greater isoprenaline‐induced vasodilatation through nitric oxide signalling in comparison to males (Riedel et al., 2019). We previously discovered that nitric oxide synthase is a major player in mediating β‐adrenergic cutaneous vasodilatation in young men (Fujii et al., 2017c).…”

“…This was evidenced by the following findings: (i) ageing had no effect on the magnitude of prostacyclin‐mediated cutaneous vasodilatation in men (Fujii, Notley, Minson, & Kenny, 2016b), whereas it augmented this vasodilatation in women (Fujii, McNeely, Nishiyasu, & Kenny, 2017d); (ii) ageing attenuated ATP‐mediated cutaneous vasodilatation in men (Fujii et al., 2018), but augmented this vasodilatation in women (Fujii et al., 2019b); and (iii) ageing attenuated low‐to‐moderate levels of muscarinic‐mediated sweating in men, whereas reductions were only observed at high levels of muscarinic‐mediated sweating in women (Fujii et al., 2019a). Furthermore, oestrogen is thought to be an important modulator of β‐adrenergic receptor expression in women, which might underlie sex‐dependent differences in cutaneous end‐organ responses to β‐adrenergic agonists (Riedel et al., 2019). Taken together, it is therefore plausible that the effects of ageing on β‐adrenergic cutaneous vasodilatation and sweating, if any, might also be modulated by sex.…”