Estrogen increases smooth muscle expression of α2C- adrenoceptors and cold-induced constriction of cutaneous arteries

A. H. Eid, K. Maiti, S. Mitra, M. A. Chotani, S. Flavahan, S. R. Bailey, C. S. Thompson-Torgerson, N. A. Flavahan

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72 Scopus citations


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 α2C-adrenoceptors (α2C-ARs) located on vascular smooth muscle cells (VSMs). Experiments were therefore performed to determine whether 17β-estradiol regulates α2C-AR expression and function in cutaneous VSMs. 17β-Estradiol (0.01-10 nmol/l) increased expression of the α2C-AR protein and the activity of the α2C-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 17β-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 17β-estradiol-induced activation of the α2C-AR gene promoter, whereas a constitutively active mutant of Rap2 increased α2C-AR promoter activity. The effects of 17β-estradiol were inhibited by the estrogen receptor (ER) antagonist, ICI-182780 (1 μmol/l), and were mimicked by a cell-impermeable form of the hormone (estrogen:BSA) or by the selective ER-α receptor agonist 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT; 10 nmol/l) or the selective ER-β receptor agonist 2,3-bis(4-hydroxyphenyl)- propionitrile (DPN; 10 nmol/l). Therefore, 17β-estradiol increased expression of α2C-ARs by interacting with cell surface receptors to cause a cAMP/Rap2-dependent increase in α2C-AR transcription. In mouse tail arteries, 17β-estradiol (10 nmol/l) increased α2C-AR expression and selectively increased the cold-induced amplification of α2-AR constriction, which is mediated by α2C-ARs. An estrogen-dependent increase in expression of cold-sensitive α2C-ARs may contribute to the increased activity of cold-induced vasoconstriction under estrogen-replete conditions.

Original languageEnglish (US)
Pages (from-to)H1955-H1961
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number3
StatePublished - Sep 2007


  • Adenosine 3′,5′-cyclic monophosphate
  • Estrogen receptors
  • Rap1
  • Rap2
  • Raynaud's phenomenon

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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