© 2000 American Heart Association, Inc.
Cellular Biology |
Membrane Estrogen Receptor Engagement Activates Endothelial Nitric Oxide Synthase via the PI3-Kinase–Akt Pathway in Human Endothelial Cells
From the Division of Cardiovascular Medicine and Molecular Cardiobiology, Boyer Center for Molecular Medicine (M.P.H., D.S., K.S.R., M.C., J.R.B.) and Department of Pharmacology (D.F., M.M.-R., W.C.S.), Yale University School of Medicine, New Haven, Conn.
Correspondence to Jeffrey R. Bender, Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Ave, New Haven, CT 06536-0812. E-mail jeffrey.bender{at}yale.edu
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Abstract |
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Abstract—17ß-Estradiol (E2) is a rapid activator of endothelial nitric oxide synthase (eNOS). The product of this activation event, NO, is a fundamental determinant of cardiovascular homeostasis. We previously demonstrated that E2-stimulated endothelial NO release can occur without an increase in cytosolic Ca2+. Here we demonstrate for the first time, to our knowledge, that E2 rapidly induces phosphorylation and activation of eNOS through the phosphatidylinositol 3 (PI3)-kinase–Akt pathway. E2 treatment (10 ng/mL) of the human endothelial cell line, EA.hy926, resulted in increased NO production, which was abrogated by the PI3-kinase inhibitor, LY294002, and the estrogen receptor antagonist ICI 182,780. E2 stimulated rapid Akt phosphorylation on serine 473. As has been shown for vascular endothelial growth factor, eNOS is an E2-activated Akt substrate, demonstrated by rapid eNOS phosphorylation on serine 1177, a critical residue for eNOS activation and enhanced sensitivity to resting cellular Ca2+ levels. Adenoviral-mediated EA.hy926 transduction confirmed functional involvement of Akt, because a kinase-deficient, dominant-negative Akt abolished E2-stimulated NO release. The membrane-impermeant E2BSA conjugate, shown to bind endothelial cell membrane sites, also induced rapid Akt and consequent eNOS phosphorylation. Thus, engagement of membrane estrogen receptors results in rapid endothelial NO release through a PI3-kinase–Akt-dependent pathway. This explains, in part, the reduced requirement for cytosolic Ca2+ fluxes and describes an important pathway relevant to cardiovascular pathophysiology.
Key Words: estrogen • endothelial nitric oxide synthase • Akt • membrane receptor
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Introduction |
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Endogenous and exogenous estrogen in premenopausal and postmenopausal women, respectively, is protective against the development of atherosclerotic cardiovascular disease.1 2 The relevant biological effects of estrogen are numerous and include improvements in lipid and lipoprotein profiles as well as endothelial-dependent vasodilation stimulated by estrogen administered at physiological concentrations. Reports have described significant estrogen-stimulated increases in bioavailable NO.3 4 5 Because the antiatherogenic properties of NO are emerging, it has been proposed that the cardiovascular protective effect of estrogen is mediated through augmentation of endothelial NO production. Using a human endothelial cell (EC) in vitro model, we have previously shown that 17ß-estradiol (E2) induces endothelial NO release within minutes, is estrogen receptor (ER)–dependent and gene transcription–independent, and is the result of activation of endothelial nitric oxide synthase (eNOS).6
The regulation of eNOS activity is multifaceted. This includes regulated palmitoylation and myristoylation, which are required for eNOS partitioning into membrane caveolae and consequent function.7 8 9 10 A variety of cofactors are required for enzymatic function, including Ca2+, calmodulin, and tetrahydrobiopterin.11 12 Recently, heat shock protein 90 (Hsp90) was demonstrated through its inducible association with eNOS to be a positive regulator of enzyme activity.13 We have previously shown that rapid activation by E2 of eNOS in human EC occurs in the absence of cytosolic Ca2+ increases. E2 and shear stress are two of the few agonists that can activate eNOS in this Ca2+ flux–independent manner. However, the precise mechanism by which estrogen stimulates NO release is not known. As has been shown for other eNOS agonists, we have recently demonstrated that estrogen rapidly promotes an eNOS-Hsp90 association.14 Inhibition experiments with the Hsp90-specific agent geldanamycin confirmed that Hsp90 is required for E2-stimulated NO release. However, this has not elucidated the diminished requirement for Ca2+ in the setting of estrogen.
Recently, our laboratory15 and other studies16 17 demonstrated that the serine/threonine kinase Akt, a downstream effector of phosphatidylinositol-3-OH kinase (PI3-kinase), phosphorylates human eNOS on serine 1177 in response to varied stimuli, such as vascular endothelial growth factor (VEGF) and shear stress. This phosphorylation not only activates eNOS, but also seems to increase the efficiency of activation by Ca2+/calmodulin.18 Given the similarities between shear stress–mediated and estrogen-mediated activation of eNOS, we evaluated the ability of estrogen to activate Akt in human ECs. We now show that E2 does indeed activate eNOS through a PI3-kinase–dependent pathway. Because membrane impermeant estrogens trigger the same events, we discuss the activation pathway, from a putative, novel membrane estrogen receptor to distal components of the cascade, and its relevance in cardiovascular pathophysiology.
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Materials and Methods |
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Materials
17ß-estradiol, ß-estradiol-17-hemisuccinate:BSA (E2BSA) (
30 mol
E2:molBSA) and ionomycin were purchased from
Sigma. E2 stocks were prepared in ethanol with
final ethanol concentrations 
0.01%. LY294002 was purchased from
Calbiochem. ICI 182,780 was purchased from Zeneca Pharmaceuticals.
Stocks of LY294002 and ICI 182,780 were prepared in
Me2SO with final concentrations of
Me2SO 0.1%. Anti-eNOS (N30020) was from
Transduction Laboratories, and antiphosphorylated Akt
(pAKT), anti-Akt, and antiphosphorylated eNOS (peNOS)
were from New England Biolabs. All other reagents were purchased
from Sigma.
Cell Culture
The permanently established EA.hy926 endothelial
cell line19 was provided by CJS Edgell (University of
North Carolina). Cells were maintained in 10% FBS, which was DMEM
supplemented with 5 mmol/L hypoxanthine, 0.8 mmol/L
thymidine, and 20 µmol/L aminopterin. Human umbilical
vein endothelial cells (HUVECs) were isolated and maintained, as
previously described.6 Before E2
stimulation, cells were cultured in E2-free
medium, which was phenol-free DMEM with gelding horse serum (<1.0
pg/mL estradiol). After the initial E2
deprivation period, some cells were additionally
serum-starved for 4 to 16 hours for detection of
phosphorylated eNOS or phosphorylated
Akt in DMEM containing 0.1% fatty acid–free BSA.
NO Release Assays
NO-specific chemiluminescence, using potassium iodide and acetic
acid reflux, was used to determine the amount of
NO2- released from cell
monolayers, as previously described.15 Cells were switched
to E2-free medium for 48 hours, after when the
medium changed to HBSS supplemented with
CaCl2 (1.2 mmol/L),
MgSO4 (0.6 mmol/L), and L-arginine
(100 µmol/L) for 30 minutes before agonist stimulation. Cells
were stimulated with E2,
E2BSA, or ionomycin for 1 hour at 37°C, and
supernatants were collected for
NO2- analysis. To
address the requirements for ER engagement and the PI3-kinase pathway,
some cells were treated with ICI 182,780 or LY294002, respectively, for
1 hour before agonist stimulation. LY294002, when used in the 3- to
50-µmol/L concentration range, has been shown to be highly PI3-kinase
specific.20 21
Immunoprecipitation and Western Blotting
Cell monolayers were stimulated as described in the figure
legends. Phosphorylated Akt was detected in cell
lysates after 48-hour E2 deprivation
and overnight serum starvation. pAkt immunoblots were
stripped and blotted for total Akt. Phosphorylated eNOS
was detected after 48-hour E2
deprivation and 4-hour serum starvation from cell lysates
in solution containing (in mmol/L) Tris-HCl 20 (pH 7.4), EDTA 2.4,
Triton X-100 1%, sodium deoxycholate 1%, SDS 0.1%, NaCl 100, NaF 10,
Na3V04 1,
NaPiPO4 1, and protease inhibitor
cocktail (Roche). Lysates were incubated with anti-eNOS antibody
overnight at 4°C immunoprecipitated with protein A:protein G.
Immunoprecipitates were immunoblotted with anti-peNOS
(1:100) and anti-eNOS (1:2500) antibodies. Immunoblots were
probed with species-specific secondary antibodies coupled to
horseradish peroxidase and visualized by enhanced
chemiluminescence.
Adenoviral Infection of Cells
The recombinant adenoviruses expressing control
ß-galactosidase (ß-gal) and an Akt kinase–inactive mutant (AA-Akt)
were obtained from K. Walsh (St. Elizabeth’s Medical Center, Boston,
Mass) and were previously described.15 22 Monolayers were
incubated with recombinant adenovirus at a multiplicity of infection of
100. After infection, E2-free medium was added
for the cell recovery period followed by serum starvation in 0.1%
fatty acid–free BSA in phenol-free DMEM. Preliminary experiments with
the ß-gal encoding virus were used to established conditions optimal
for >95% cell culture transduction.
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Results |
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PI3-Kinase Inhibitor Blocks E2-Dependent NO Release
Previous studies from our laboratory15 and other studies17 have demonstrated that VEGF and shear stress can activate eNOS through a PI3-kinase/Akt-dependent pathway. After agonist stimulation of PI3-kinase, cytosolic Akt translocates to the plasma membrane where it is activated by serine and threonine phosphorylation. This membrane-activated form of Akt has been shown to specifically phosphorylate human eNOS at serine 1177, resulting in enhanced eNOS activity and increased NO release.15 17 To investigate the ability of E2 to activate the PI3-kinase pathway in EC, EA.hy926 cells were pretreated with 10 µmol/L LY294002 or vehicle for 1 hour before agonist stimulation. Cells were then stimulated with E2, ionomycin, or vehicle for 30 minutes, and the medium was collected for NO2- analysis. As shown in Figure 1
, E2
treatment of EA.hy926 cells results in a >4-fold induction of NO
release. This augmentation was completely abrogated by pretreatment
with LY294002 (Figure 1), which had no effect on basal control
levels of NO (data not shown). As demonstrated here and in previous
endothelial studies,6 14
E2-induced increased NO production in
EA.hy926 is an ER-dependent process that is completely inhibitable by
pretreatment with the pure ER antagonist ICI 182,780. This
demonstrates that E2 stimulation of EC can
dramatically augment NO release in a PI3-kinase–dependent manner
through an ER-mediated pathway.
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E2 Stimulates Downstream Targets of the PI3-Kinase
Pathway
One of the downstream targets of the PI3-kinase pathway is the
serine/threonine kinase Akt/PKB. Known Akt substrates include eNOS as
well as several proteins involved in cell survival and glucose
metabolism.23 24 Because
E2-stimulated NO release is largely
PI3-kinase–dependent, we addressed whether E2
treatment could also result in Akt activation. To test this, both
EA.hy926 and HUVEC cell lysates were prepared from
E2-stimulated or vehicle control–stimulated
cells. When using an antibody directed at the serine
473–phosphorylated, activated form of Akt,
phosphorylation was detected within 5 minutes of
E2 treatment in both cell types and persisted for
at least 30 minutes (Figure 2).
Dose-response experiments demonstrated induced
endothelial Akt activation with as little as 100 pg/mL
E2 (data not shown). These results and the
PI3-kinase inhibition data demonstrate that E2
can activate endothelial PI3-kinase, resulting
in the presumed translocation of Akt to the plasma membrane, where it
is activated by phosphorylation.
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The kinetics of E2-stimulated EC Akt
phosphorylation correlate with the rapid, nongenomic
activation of eNOS we have reported previously.6 14 eNOS
has been classically described as a
Ca2+/calmodulin-dependent
enzyme.12 However, we have demonstrated that the
E2-induced increase in EC-NO release occurs
without a cytosolic Ca2+ increase and does not
alter the amount of eNOS-associated
calmodulin.14 Recently, our
laboratories15 and other studies17 have
demonstrated that the phosphorylation of human eNOS
serine 1177 (serine 1179 in bovine eNOS) by Akt lowers the apparent
Ca2+/calmodulin requirements of the
enzyme. Thus, using an antibody specific for this Akt substrate,
phosphorylated eNOS site, Western blot analyses
were performed to determine whether E2
stimulation does, in fact, result in EC eNOS
phosphorylation. ECs were
E2-deprived and serum-starved before stimulation
with E2 or vehicle control. As shown in Figure 3A, specifically
phosphorylated eNOS was easily detected within 5
minutes of E2 exposure.
Phosphorylated eNOS persists for at least 30 minutes
and is phosphorylated to the same extent as
endothelial cells treated with VEGF (Figure 3B),
a known inducer of bovine eNOS
phosphorylation.15 Thus, the kinetics of
E2-stimulated Akt
phosphorylation, eNOS phosphorylation,
and EC-NO release are all consistent.
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Dominant-Negative Form of Akt Blocks E2-Stimulated
NO Release
To directly establish that the E2-triggered
signal transduction pathway resulting in NO release proceeds through
Akt, EA.hy926 cells were transduced with adenoviral vectors encoding an
AA-Akt or control ß-gal. AA-Akt has been shown to block
VEGF-stimulated NO release.15 Additionally,
kinase-inactive Akt is unable to phosphorylate eNOS in
response to shear stress and thus is unable to enhance NO release in
that setting.17 Cells were infected with the adenovirus
for 2 hours, incubated for 24 hours in
E2-deficient serum, and kept serum-free for an
additional 24 hours. As has been described with other ECs, the
transduction efficiency was very high, with positive ß-gal staining
in >95% of ß-gal–transduced cells (data not shown). Cells infected
with control (ß-gal) exhibited a 2.25-fold increase in
E2-stimulated NO release similar to the 2.5-fold
induction seen in noninfected cells (Figure 4), whereas AA-Akt expression largely
abrogated E2-stimulated NO production.
This demonstrates that functionally active Akt is required for
E2-stimulated NO release.
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Cell-Impermeant E2 Activates the
PI3-Kinase/Akt Pathway
The existence of cell-surface steroid hormone receptors has been
debated. Recently, membrane progesterone receptors have been detected
and shown to be physiologically
active.25 In addition, overexpression of ER
and ß in
Chinese hamster ovary cells results in the detection of a few surface
ERs that can respond to E2.26
E2 conjugated to BSA is membrane-impermeant and
has been used to detect surface binding sites for
E2.14 27 28 We have described an
apparent EC-membrane ER capable of rapidly inducing NO release and
activating mitogen-activated protein (MAP) kinase (ERK
1/2).29 E2BSA was thus used to
determine whether the PI3-kinase/Akt pathway can be activated
by engagement of a surface ER. Cell monolayers were stimulated with
E2BSA or vehicle in the presence of excess fatty
acid–free BSA. Figure 5 demonstrates
that E2BSA does trigger Akt
phosphorylation. Similar to that seen with
cell-permeant E2,
E2BSA-stimulated Akt
phosphorylation occurs within 5 minutes (Figure 5) and persists for at least 30 minutes (data not shown).
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To again determine whether this Akt activation is required for NO
release, ECs were AA-Akt–transduced or ß-gal–transduced with the
respective adenovirus before stimulation with
E2BSA or vehicle control. Figure 6 demonstrates that cells overexpressing
kinase-inactive Akt were unable to generate any
E2-stimulated NO release, whereas control
ß-gal–transduced cells maintained an excellent response to
E2BSA. This indicates that
E2 can stimulate an increase in NO via a surface
receptor that signals through the PI3-kinase/Akt pathway. As expected,
E2BSA triggered the critical, Akt-induced
phosphorylation on eNOS serine 1177 within 5 minutes
(Figure 7). Thus, all the activation
events induced by free E2 can be reproduced by
engagement of a surface ER.
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Discussion |
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The ability of estrogen to induce a rapid, endothelial- and NO-dependent vasodilatory response has been demonstrated in several systems,6 14 30 but the precise activating, molecular mechanism remains largely unknown. We have previously shown that E2 can rapidly induce human umbilical vein EC-NO release without requiring increases in cytosolic Ca2+ (ie, occurring at resting EC Ca2+ levels).6 Here, we demonstrate that E2 activates the PI3-kinase/Akt pathway in human EC. The relevance of this activation is confirmed by abrogation of E2-stimulated NO release with pharmacological inhibition of PI3-kinase as well as recombinant expression of an activation-deficient, dominant-negative Akt. Additional evidence for the E2-triggered activation includes rapid phosphorylation of the critical serine 473 Akt residue and consequent activating phosphorylation of serine 1177 on eNOS.
eNOS is a Ca2+ and calmodulin-dependent enzyme, and its regulated activation by agonists such as histamine and acetylcholine seems to require a stimulated rise in intracellular Ca2+.31 However, recent evidence supports that several stimuli, including fluid shear stress,32 insulin,33 and estrogen,6 can activate eNOS and augment NO release in the absence of identifiable Ca2+ fluxes and in the setting of Ca2+ chelation. This apparent paradox has been difficult to reconcile and, in the context of estrogen, has been debated.34 Recently, our laboratories15 and other studies16 17 have shown that Akt phosphorylates human eNOS on a critical serine 1177 (1179 in bovine eNOS). Altering the charge on this residue, either through Akt-induced phosphorylation or by mutagenesis-based substitution with aspartate, is associated with an increase in NO production and enzyme activation at much lower Ca2+ and calmodulin concentrations.15 16 17 That is, Akt-induced eNOS phosphorylation greatly increases the activity of eNOS at resting Ca2+ concentrations. This is based, in part, on a faster rate of electron flux through the eNOS reductase domain and a reduced calmodulin dissociation from eNOS when Ca2+ levels are low.18 Phosphorylation may confer a conformational alteration on the interaction of calmodulin with the 45 amino acid autoinhibitory flavin mononucleotide insert domain or in the carboxy tail, thereby effecting disinhibition. Our results clearly demonstrate that E2 stimulates human endothelial Akt activation and eNOS phosphorylation. The findings that PI3-kinase–dependent Akt activation is not Ca2+-dependent and that this specific serine 1177 phosphorylation enhances eNOS Ca2+ sensitivity are consistent with our previous data that estrogen-stimulated endothelial NO release does not require a rise in free intracellular Ca2+ and provide the first mechanistic explanation of how this may occur.
The signaling cascade leading to PI3-kinase/Akt activation by E2 is presently unknown. There are many examples of growth factors stimulating hormone-independent estrogen receptor–mediated events through phosphorylation of the critical ER transactivation function domain-1.35 36 However, details of the converse have not been defined. That is, the PI3-kinase/Akt activation by estrogen demonstrated here, and inhibited by conventional ER antagonists, depicts rapid growth factor receptor–type responses induced by a steroid hormone. In the mouse uterus, estrogen has been shown to trigger the tyrosine phosphorylation of insulin-like growth factor receptor-1 (IGF-1R), as well as tyrosine phosphorylation of the docking substrate IRS-1 and consequent IGF-1R/IRS-1/PI3-kinase p85 complex formation.37 38 This induced recruitment of the regulatory unit of PI3-kinase is sufficient to initiate enzyme activation. Much of the estrogen-induced p85-IGF-1R association was absent in IGF-1–deficient mice, suggesting that a majority of this pathway activation is a consequence of E2-stimulated IGF-1 synthesis. However, residual induced p85-IGF-1R complexes remained in the absence of IGF-1. Estrogen-induced recruitment of p85 to tyrosine kinase growth factor receptors could be responsible for the signaling events described in this study.
Other potential cascades should be considered on the basis of several analogies between fluid shear stress–stimulated and estrogen-stimulated eNOS activation, including the induction of relative Ca2+ independence. Shear stress activates Akt in a PI3-kinase–dependent fashion, and consequent NO production is inhibited by the PI3-kinase inhibitor wortmannin.17 Shear stress induces a clustering of the VEGF receptor Flk-1 and its rapid tyrosine phosphorylation and association with the adapter protein Shc, which can result in Ras activation and subsequent MAP kinase induction through the assembly of Shc/Grb2/SOS complexes.39 Our laboratories14 and other studies40 have demonstrated a rapid MAP kinase activation induced by E2 in ECs. In addition to its role in the MAP kinase pathway, GTP-bound Ras can also activate PI3-kinase.41 This is another potential signaling pathway by which E2 could trigger EC-NO release.
We recently demonstrated that Hsp90 is rapidly recruited to eNOS on endothelial treatment with E2.14 Geldanamycin, which binds to the ATP-binding site of Hsp90 and inhibits its function, abrogates E2-stimulated EC-NO release. The relationship between Hsp90 recruitment and Akt activation, both triggered by E2 and required for stimulated eNOS activation, remains unclear. Herbimycin A, in the same pharmacological class as geldanamycin, does not block shear stress–induced Akt activation. Considering the analogy to estrogen responses, this suggests either that functional Hsp90-eNOS association is a critical downstream mediator of eNOS activation or that the pathways by which Akt and Hsp90 regulate eNOS activity, as induced by estrogen, are both required but independent. We are presently investigating the interplay between estrogen-induced Hsp90-eNOS association and modulation of eNOS by Akt.
Finally, one must consider the most proximal signal transduction
event in response to E2: that of ER engagement.
The events described occur rapidly, are inhibited by conventional ER
antagonists, and are consistent with rapid
transmembrane signaling. Our results demonstrate for the first time
that PI3-kinase and Akt activation can be triggered with the cell
impermeant E2BSA conjugate. We have used this
conjugate extensively, including after charcoal extraction of any free
E2, and determined E2BSA
binding sites on human EC membranes that are competitively blocked by
conventional ER antagonists and free
E2.29 As opposed to uterine and
breast cells, in which estrogen has been shown to activate
PI3-kinase,38 42 EA.hy926 ECs, used in these experiments,
do not express the traditional 66 kDa ER (or ERß) nor are they
able to undergo the normal E2-stimulated,
ER-dependent gene transactivation (Reference 2929 and unpublished data,
July 2000). However, they do express a 45-kDa protein,
immunoreactive with an anti–C-terminal ER antibody, which seems to
correlate with intact rapid signaling responses.29
Experiments to identify this molecule are presently underway.
In summary, we have found that the mechanism by which estrogen stimulates endothelial NO production involves a rapid, PI3-kinase–dependent activation of Akt and consequent serine phosphorylation of eNOS. These activation events occur after engagement of membrane receptors for estrogen. This explains the emerging paradigm relating rapid, estrogen-stimulated endothelial signaling, enhanced eNOS sensitivity to cytosolic Ca2+, and unconventional estrogen receptors. Additional definition of these receptors and the proximal signaling events leading to Akt activation will provide opportunities for specialized therapeutic interventions in cardiovascular disease.
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Acknowledgments |
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This work was supported by National Institutes of Health grants HL61782 (to J.R.B) and HL61371 and HL64793 (to W.C.S.). We thank Lynn O’Donnell for technical assistance, Dana Brenckle for manuscript preparation, and all those who provided valuable reagents, including Dr Ken Walsh for generously providing the adenoviral constructs.
Received August 7, 2000; revision received September 1, 2000; accepted September 6, 2000.
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 R. I. Fernando and J. Wimalasena Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt Mol. Biol. Cell, July 1, 2004; 15(7): 3266 - 3284. [Abstract] [Full Text] [PDF]
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 W. C. Sessa eNOS at a glance J. Cell Sci., May 15, 2004; 117(12): 2427 - 2429. [Full Text] [PDF]
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F. Barletta, C.-W. Wong, C. McNally, B. S. Komm, B. Katzenellenbogen, and B. J. Cheskis Characterization of the Interactions of Estrogen Receptor and MNAR in the Activation of cSrc Mol. Endocrinol., May 1, 2004; 18(5): 1096 - 1108. [Abstract] [Full Text] [PDF]
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 M. Esfandiarei, H. Luo, B. Yanagawa, A. Suarez, D. Dabiri, J. Zhang, and B. M. McManus Protein Kinase B/Akt Regulates Coxsackievirus B3 Replication through a Mechanism Which Is Not Caspase Dependent J. Virol., April 15, 2004; 78(8): 4289 - 4298. [Abstract] [Full Text] [PDF]
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J. M. Orshal and R. A. Khalil Gender, sex hormones, and vascular tone Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2004; 286(2): R233 - R249. [Abstract] [Full Text] [PDF]
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F. L. Wynne, J. A. Payne, A. E. Cain, J. F. Reckelhoff, and R. A. Khalil Age-Related Reduction in Estrogen Receptor-Mediated Mechanisms of Vascular Relaxation in Female Spontaneously Hypertensive Rats Hypertension, February 1, 2004; 43(2): 405 - 412. [Abstract] [Full Text] [PDF]
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Y. Xu, R. J. Traystman, P. D. Hurn, and M. M. Wang Membrane Restraint of Estrogen Receptor {alpha} Enhances Estrogen-Dependent Nuclear Localization and Genomic Function Mol. Endocrinol., January 1, 2004; 18(1): 86 - 96. [Abstract] [Full Text] [PDF]
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D.-b. Chen, I. M. Bird, J. Zheng, and R. R. Magness Membrane Estrogen Receptor-Dependent Extracellular Signal-Regulated Kinase Pathway Mediates Acute Activation of Endothelial Nitric Oxide Synthase by Estrogen in Uterine Artery Endothelial Cells Endocrinology, January 1, 2004; 145(1): 113 - 125. [Abstract] [Full Text] [PDF]
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P.-F. Chen and K. K. Wu Structural Elements Contribute to the Calcium/Calmodulin Dependence on Enzyme Activation in Human Endothelial Nitric-oxide Synthase J. Biol. Chem., December 26, 2003; 278(52): 52392 - 52400. [Abstract] [Full Text] [PDF]
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 C. S. Watson and B. Gametchu Proteins of Multiple Classes May Participate in Nongenomic Steroid Actions Experimental Biology and Medicine, December 1, 2003; 228(11): 1272 - 1281. [Abstract] [Full Text] [PDF]
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S. L. Liu, S. Schmuck, J. Z. Chorazcyzewski, R. Gros, and R. D. Feldman Aldosterone Regulates Vascular Reactivity: Short-Term Effects Mediated by Phosphatidylinositol 3-Kinase-Dependent Nitric Oxide Synthase Activation Circulation, November 11, 2003; 108(19): 2400 - 2406. [Abstract] [Full Text] [PDF]
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D. P. Holden, J. E. Cartwright, S. S. Nussey, and G. S. J. Whitley Estrogen Stimulates Dimethylarginine Dimethylaminohydrolase Activity and the Metabolism of Asymmetric Dimethylarginine Circulation, September 30, 2003; 108(13): 1575 - 1580. [Abstract] [Full Text] [PDF]
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S. Takahashi and M. E. Mendelsohn Synergistic Activation of Endothelial Nitric-oxide Synthase (eNOS) by HSP90 and Akt: CALCIUM-INDEPENDENT eNOS ACTIVATION INVOLVES FORMATION OF AN HSP90-Akt-CaM-BOUND eNOS COMPLEX J. Biol. Chem., August 15, 2003; 278(33): 30821 - 30827. [Abstract] [Full Text] [PDF]
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K. Sasaki, M. Sato, and Y. Umezawa Fluorescent Indicators for Akt/Protein Kinase B and Dynamics of Akt Activity Visualized in Living Cells J. Biol. Chem., August 15, 2003; 278(33): 30945 - 30951. [Abstract] [Full Text] [PDF]
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R. Chatrath, K. L. Ronningen, S. R. Severson, P. LaBreche, M. Jayachandran, M. P. Bracamonte, and V. M. Miller Endothelium-dependent responses in coronary arteries are changed with puberty in male pigs Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1168 - H1176. [Abstract] [Full Text] [PDF]
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 R. M. LOSEL, E. FALKENSTEIN, M. FEURING, A. SCHULTZ, H.-C. TILLMANN, K. ROSSOL-HASEROTH, and M. WEHLING Nongenomic Steroid Action: Controversies, Questions, and Answers Physiol Rev, July 1, 2003; 83(3): 965 - 1016. [Abstract] [Full Text] [PDF]
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G. E. Stoica, T. F. Franke, A. Wellstein, F. Czubayko, H.-J. List, R. Reiter, E. Morgan, M. B. Martin, and A. Stoica Estradiol Rapidly Activates Akt via the ErbB2 Signaling Pathway Mol. Endocrinol., May 1, 2003; 17(5): 818 - 830. [Abstract] [Full Text] [PDF]
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L. Li, M. P. Haynes, and J. R. Bender Plasma membrane localization and function of the estrogen receptor alpha variant (ER46) in human endothelial cells PNAS, April 15, 2003; 100(8): 4807 - 4812. [Abstract] [Full Text] [PDF]
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R. Barsacchi, C. Perrotta, S. Bulotta, S. Moncada, N. Borgese, and E. Clementi Activation of Endothelial Nitric-Oxide Synthase by Tumor Necrosis Factor-alpha : A Novel Pathway Involving Sequential Activation of Neutral Sphingomyelinase, Phosphatidylinositol-3' kinase, and Akt Mol. Pharmacol., April 1, 2003; 63(4): 886 - 895. [Abstract] [Full Text] [PDF]
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P. Dan, J. C. Y. Cheung, D. R. L. Scriven, and E. D. W. Moore Epitope-dependent localization of estrogen receptoralpha , but not -beta , in en face arterial endothelium Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1295 - H1306. [Abstract] [Full Text] [PDF]
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S. Takahashi and M. E. Mendelsohn Calmodulin-dependent and -independent Activation of Endothelial Nitric-oxide Synthase by Heat Shock Protein 90 J. Biol. Chem., March 7, 2003; 278(11): 9339 - 9344. [Abstract] [Full Text] [PDF]
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R. Thuillier, Y. Wang, and M. Culty Prenatal Exposure to Estrogenic Compounds Alters the Expression Pattern of Platelet-Derived Growth Factor Receptors {alpha} and {beta} in Neonatal Rat Testis: Identification of Gonocytes as Targets of Estrogen Exposure Biol Reprod, March 1, 2003; 68(3): 867 - 880. [Abstract] [Full Text] [PDF]
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H. Harada, K. P. Pavlick, I. N. Hines, D. J. Lefer, J. M. Hoffman, S. Bharwani, R. E. Wolf, and M. B. Grisham Sexual dimorphism in reduced-size liver ischemia and reperfusion injury in mice: Role of endothelial cell nitric oxide synthase PNAS, January 21, 2003; 100(2): 739 - 744. [Abstract] [Full Text] [PDF]
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M. P. Haynes, L. Li, D. Sinha, K. S. Russell, K. Hisamoto, R. Baron, M. Collinge, W. C. Sessa, and J. R. Bender Src Kinase Mediates Phosphatidylinositol 3-Kinase/Akt-dependent Rapid Endothelial Nitric-oxide Synthase Activation by Estrogen J. Biol. Chem., January 17, 2003; 278(4): 2118 - 2123. [Abstract] [Full Text] [PDF]
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G. A. Figtree, D. McDonald, H. Watkins, and K. M. Channon Truncated Estrogen Receptor {alpha} 46-kDa Isoform in Human Endothelial Cells: Relationship to Acute Activation of Nitric Oxide Synthase Circulation, January 7, 2003; 107(1): 120 - 126. [Abstract] [Full Text] [PDF]
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I. Fleming and R. Busse Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2003; 284(1): R1 - R12. [Abstract] [Full Text] [PDF]
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C. Stirone, S. P. Duckles, and D. N. Krause Multiple forms of estrogen receptor-alpha in cerebral blood vessels: regulation by estrogen Am J Physiol Endocrinol Metab, January 1, 2003; 284(1): E184 - E192. [Abstract] [Full Text] [PDF]
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C. E. Ihionkhan, K. L. Chambliss, L. L. Gibson, L. D. Hahner, M. E. Mendelsohn, and P. W. Shaul Estrogen Causes Dynamic Alterations in Endothelial Estrogen Receptor Expression Circ. Res., November 1, 2002; 91(9): 814 - 820. [Abstract] [Full Text] [PDF]
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K. L. Chambliss and P. W. Shaul Estrogen Modulation of Endothelial Nitric Oxide Synthase Endocr. Rev., October 1, 2002; 23(5): 665 - 686. [Abstract] [Full Text] [PDF]
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 A. W. WYATT, J. R. STEINERT, C. P. D. WHEELER-JONES, A. J. MORGAN, D. SUGDEN, J. D. PEARSON, L. SOBREVIA, and G. E. MANN Early activation of the p42/p44MAPK pathway mediates adenosine-induced nitric oxide production in human endothelial cells: a novel calcium-insensitive mechanism FASEB J, October 1, 2002; 16(12): 1584 - 1594. [Abstract] [Full Text] [PDF]
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L. Bjornstrom and M. Sjoberg Signal Transducers and Activators of Transcription as Downstream Targets of Nongenomic Estrogen Receptor Actions Mol. Endocrinol., October 1, 2002; 16(10): 2202 - 2214. [Abstract] [Full Text] [PDF]
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K. K. Koh Effects of estrogen on the vascular wall: vasomotor function and inflammation Cardiovasc Res, September 1, 2002; 55(4): 714 - 726. [Full Text] [PDF]
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M.-H. Zou, X.-Y. Hou, C.-M. Shi, D. Nagata, K. Walsh, and R. A. Cohen Modulation by Peroxynitrite of Akt- and AMP-activated Kinase-dependent Ser1179 Phosphorylation of Endothelial Nitric Oxide Synthase J. Biol. Chem., August 30, 2002; 277(36): 32552 - 32557. [Abstract] [Full Text] [PDF]
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