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, Nicholas Flavahan

Research output: Contribution to journalArticle

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 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)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume293
Issue number3
DOIs
StatePublished - Sep 2007

Fingerprint

Constriction
Adrenergic Receptors
Smooth Muscle
Estradiol
Estrogens
Arteries
Skin
Estrogen Receptors
Transfection
Raynaud Disease
Cell Surface Receptors
Vasoconstriction
Vascular Smooth Muscle
GTP-Binding Proteins
NAD
Genes
Smooth Muscle Myocytes
Tail
Hormones
Proteins

Keywords

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

ASJC Scopus subject areas

  • Physiology

Cite this

Estrogen increases smooth muscle expression of α2C- adrenoceptors and cold-induced constriction of cutaneous arteries. / Eid, A. H.; Maiti, K.; Mitra, S.; Chotani, M. A.; Flavahan, S.; Bailey, S. R.; Thompson-Torgerson, C. S.; Flavahan, Nicholas.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 293, No. 3, 09.2007.

Research output: Contribution to journalArticle

Eid, A. H. ; Maiti, K. ; Mitra, S. ; Chotani, M. A. ; Flavahan, S. ; Bailey, S. R. ; Thompson-Torgerson, C. S. ; Flavahan, Nicholas. / Estrogen increases smooth muscle expression of α2C- adrenoceptors and cold-induced constriction of cutaneous arteries. In: American Journal of Physiology - Heart and Circulatory Physiology. 2007 ; Vol. 293, No. 3.
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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 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.",
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AU - Maiti, K.

AU - Mitra, S.

AU - Chotani, M. A.

AU - Flavahan, S.

AU - Bailey, S. R.

AU - Thompson-Torgerson, C. S.

AU - Flavahan, Nicholas

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N2 - 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.

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