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

Department of Pharmacology, College of Medicine, University of California, Irvine, Irvine, California

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 17-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 ER and caveolin-1 immunoreactivity at the plasma membrane of endothelial cells lining cerebral arteries. Treatment with 10 nM 17-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 -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, 17-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. ER protein (66 and 50 kDa) coimmunoprecipitated with eNOS as well as with the p85 regulatory subunit of PI-3 kinase, further implicating ER 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.

Address correspondence to: Dr. Diana N. Krause, Department of Pharmacology, College of Medicine, University of California, Irvine, Irvine, CA 92697-4625. E-mail: dnkrause{at}uci.edu

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