Estrogen increases smooth muscle expression of α_2C-adrenoceptors and cold-induced constriction of cutaneous arteries

Abstract

Raynaud's phenomenon, which is characterized by intense cold-induced constriction of cutaneous arteries, is more common in women compared with men. Cold-induced constriction is mediated in part by enhanced activity of alpha(2C)-adrenoceptors (alpha(2C)-ARs) located on vascular smooth muscle cells (VSMs). Experiments were therefore performed to determine whether 17beta-estradiol regulates alpha(2C)-AR expression and function in cutaneous VSMs. 17beta-Estradiol (0.01-10 nmol/l) increased expression of the alpha(2C)-AR protein and the activity of the alpha(2C)-AR gene promoter in human cultured dermal VSMs, which was assessed following transient transfection of the cells with a promoter-reporter construct. The effect of 17beta-estradiol was associated with increased accumulation of cAMP and activation of the cAMP-responsive Rap2 GTP-binding protein. Transient transfection of VSMs with a dominant-negative mutant of Rap2 inhibited the 17beta-estradiol-induced activation of the alpha(2C)-AR gene promoter, whereas a constitutively active mutant of Rap2 increased alpha(2C)-AR promoter activity. The effects of 17beta-estradiol were inhibited by the estrogen receptor (ER) antagonist, ICI-182780 (1 micromol/l), and were mimicked by a cell-impermeable form of the hormone (estrogen:BSA) or by the selective ER-alpha receptor agonist 4,4',4'''-(4-propyl-[(1)H]-pyrazole-1,3,5-triyl)tris-phenol (PPT; 10 nmol/l) or the selective ER-beta receptor agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN; 10 nmol/l). Therefore, 17beta-estradiol increased expression of alpha(2C)-ARs by interacting with cell surface receptors to cause a cAMP/Rap2-dependent increase in alpha(2C)-AR transcription. In mouse tail arteries, 17beta-estradiol (10 nmol/l) increased alpha(2C)-AR expression and selectively increased the cold-induced amplification of alpha(2)-AR constriction, which is mediated by alpha(2C)-ARs. An estrogen-dependent increase in expression of cold-sensitive alpha(2C)-ARs may contribute to the increased activity of cold-induced vasoconstriction under estrogen-replete conditions.

Sex Difference in Peripheral Arterial Response to Cold Exposure

“…25 Recently, it was reported that expression of the adrenergic 2C-receptor is enhanced by estrogen. 26 Although it was seen in cutaneous arterioles in vivo, estrogen may enhance the expression of adrenergic 2C receptor in deep arteries, which in females showed less expansion against cold exposure in the present study.…”

Impaired transient vasodilation and increased vasoconstriction to digital local cooling in primary Raynaud's phenomenon

“…This may reflect the influence of estrogen in the prevalence of RP, higher in women than in men, and decreasing in postmenopausal women. Of interest, a recent study (9) has shown that estrogen can increase the expression of ␣ 2C -adrenoreceptors and also increased ␣ 2 -adrenoreceptor-mediated constriction during exposure to cold. In the present study, we were not able to observe any difference between women according to their hormonal status, but the sample size was too small to address this issue.…”

Vestibulosympathetic reflex during the early follicular and midluteal phases of the menstrual cycle

“…Eid et al (5) reported that the treatment of 17␤-estradiol on human cultured vascular muscle cells interacted with cell surface receptors to cause an increase in ␣ 2C -adrenoceptor transcription. Thus, the activation of the vestibulosympathetic reflex may elicit differences in vascular transduction at times of low and high estrogen due to the expression of postsynaptic ␣ 2 -adrenoceptors on the smooth muscle cells.…”