title: Estrogen increases smooth muscle expression of alpha2C-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.
authors.affiliation: Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Eid
authors.forename: K
authors.initials: K
authors.lastname: Maiti
authors.forename: S
authors.initials: S
authors.lastname: Mitra
authors.forename: M A
authors.initials: MA
authors.lastname: Chotani
authors.forename: S
authors.initials: S
authors.lastname: Flavahan
authors.forename: S R
authors.initials: SR
authors.lastname: Bailey
authors.forename: C S
authors.initials: CS
authors.lastname: Thompson-Torgerson
authors.forename: N A
authors.initials: NA
authors.lastname: Flavahan
mesh_terms: D001158:Arteries / Q000378:metabolism*; D002478:Cells, Cultured; D003080:Cold Temperature; D020405:Dermis / Q000098:blood supply*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D011928:Raynaud Disease / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology*; D020668:rap GTP-Binding Proteins / Q000378:metabolism
chemical_list: C547774:ADRA2C protein, human; C547775:Adra2c protein, mouse; D004965:Estrogen Antagonists; D018341:Receptors, Adrenergic, alpha-2; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D009569:Nitric Oxide; D004958:Estradiol; C116756:RAP2A protein, human; D020668:rap GTP-Binding Proteins