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Molecular Pharmacology

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Research ArticleArticle

Estrogen Receptor Activation of Phosphoinositide-3 Kinase, Akt, and Nitric Oxide Signaling in Cerebral Blood Vessels: Rapid and Long-Term Effects

Chris Stirone, Amin Boroujerdi, Sue P. Duckles and Diana N. Krause
Molecular Pharmacology January 2005, 67 (1) 105-113; DOI: https://doi.org/10.1124/mol.104.004465
Chris Stirone
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Amin Boroujerdi
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Sue P. Duckles
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Diana N. Krause
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Abstract

Estrogen receptor regulation of nitric oxide production by vascular endothelium may involve rapid, membrane-initiated signaling pathways in addition to classic genomic mechanisms. In this study, we demonstrate using intact cerebral blood vessels that 17β-estradiol rapidly activates endothelial nitric-oxide synthase (eNOS) via a phosphoinositide-3 (PI-3) kinase-dependent pathway. The effect is mediated by estrogen receptors (ERs), consistent with colocalization of ERα and caveolin-1 immunoreactivity at the plasma membrane of endothelial cells lining cerebral arteries. Treatment with 10 nM 17β-estradiol for 30 min increased NO production, as measured by total nitrite assay, in cerebral vessels isolated from ovariectomized rats. This effect was significantly decreased by membrane cholesterol depletion with β-methyl-cyclodextrin, the ER antagonist ICI 182,780 [fulvestrant (Faslodex)], and two inhibitors of PI-3 kinase: wortmannin and LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride]. In parallel with NO production, 17β-estradiol treatment rapidly increased phosphorylation of both eNOS (p-eNOS) and Akt (p-Akt). PI-3 kinase inhibitors also blocked the latter effects; together, these data are consistent with ER activation of the PI-3 kinase-p-Akt-p-eNOS pathway. ERα protein (66 and 50 kDa) coimmunoprecipitated with eNOS as well as with the p85α regulatory subunit of PI-3 kinase, further implicating ERα in kinase activation of eNOS. Little is known regarding the effects of estrogen on cellular kinase pathways in vivo; therefore, we compared cerebral blood vessels isolated from ovariectomized rats that were either untreated or given estrogen replacement for 4 weeks. Long-term estrogen exposure increased levels of cerebrovascular p-Akt and p-eNOS as well as basal NO production. Thus, in addition to the rapid activation of PI-3 kinase, p-Akt, and p-eNOS, estrogen signaling via nontranscriptional, kinase mechanisms has long-term consequences for vascular function.

  • Received July 1, 2004.
  • Accepted October 19, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 67 (1)
Molecular Pharmacology
Vol. 67, Issue 1
1 Jan 2005
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Research ArticleArticle

Estrogen Receptor Activation of Phosphoinositide-3 Kinase, Akt, and Nitric Oxide Signaling in Cerebral Blood Vessels: Rapid and Long-Term Effects

Chris Stirone, Amin Boroujerdi, Sue P. Duckles and Diana N. Krause
Molecular Pharmacology January 1, 2005, 67 (1) 105-113; DOI: https://doi.org/10.1124/mol.104.004465

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Research ArticleArticle

Estrogen Receptor Activation of Phosphoinositide-3 Kinase, Akt, and Nitric Oxide Signaling in Cerebral Blood Vessels: Rapid and Long-Term Effects

Chris Stirone, Amin Boroujerdi, Sue P. Duckles and Diana N. Krause
Molecular Pharmacology January 1, 2005, 67 (1) 105-113; DOI: https://doi.org/10.1124/mol.104.004465
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