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Circulation Research. 2000;87:677-682

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(Circulation Research. 2000;87:677.)
© 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

M. Page Haynes, Diviya Sinha, Kerry Strong Russell, Mark Collinge, David Fulton, Manuel Morales-Ruiz, William C. Sessa, Jeffrey R. Bender

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

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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H. Aramoto, J. W. Breslin, P. J. Pappas, R. W. Hobson II, and W. N. Duran
Vascular endothelial growth factor stimulates differential signaling pathways in in vivo microcirculation
Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1590 - H1598.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
K. L. Hamilton, F.N. Mbai, S. Gupta, and A.A. Knowlton
Estrogen, Heat Shock Proteins, and NF{kappa}B in Human Vascular Endothelium
Arterioscler Thromb Vasc Biol, September 1, 2004; 24(9): 1628 - 1633.
[Abstract] [Full Text] [PDF]


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Biol. Reprod.Home page
O. Guzeloglu Kayisli, U. A. Kayisli, G. Luleci, and A. Arici
In Vivo and In Vitro Regulation of Akt Activation in Human Endometrial Cells Is Estrogen Dependent
Biol Reprod, September 1, 2004; 71(3): 714 - 721.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Heart Circ. Physiol.Home page
Y. Wang, N. Ahmad, M. Kudo, and M. Ashraf
Contribution of Akt and endothelial nitric oxide synthase to diazoxide-induced late preconditioning
Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1125 - H1131.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Renal Physiol.Home page
P. A. Ortiz, N. J. Hong, and J. L. Garvin
Luminal flow induces eNOS activation and translocation in the rat thick ascending limb. II. Role of PI3-kinase and Hsp90
Am J Physiol Renal Physiol, August 1, 2004; 287(2): F281 - F288.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
D. Fulton, R. Babbitt, S. Zoellner, J. Fontana, L. Acevedo, T. J. McCabe, Y. Iwakiri, and W. C. Sessa
Targeting of Endothelial Nitric-oxide Synthase to the Cytoplasmic Face of the Golgi Complex or Plasma Membrane Regulates Akt- Versus Calcium-dependent Mechanisms for Nitric Oxide Release
J. Biol. Chem., July 16, 2004; 279(29): 30349 - 30357.
[Abstract] [Full Text] [PDF]


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Mol. Biol. CellHome page
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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J. Cell Sci.Home page
W. C. Sessa
eNOS at a glance
J. Cell Sci., May 15, 2004; 117(12): 2427 - 2429.
[Full Text] [PDF]


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Mol. Endocrinol.Home page
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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J. Virol.Home page
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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Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
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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HypertensionHome page
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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Mol. Endocrinol.Home page
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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EndocrinologyHome page
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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J. Biol. Chem.Home page
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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Exp. Biol. Med.Home page
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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CirculationHome page
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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CirculationHome page
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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J. Biol. Chem.Home page
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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J. Biol. Chem.Home page
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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Am. J. Physiol. Heart Circ. Physiol.Home page
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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Physiol. Rev.Home page
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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Mol. Endocrinol.Home page
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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Proc. Natl. Acad. Sci. USAHome page
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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Mol. Pharmacol.Home page
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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Am. J. Physiol. Heart Circ. Physiol.Home page
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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J. Biol. Chem.Home page
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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Biol. Reprod.Home page
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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Proc. Natl. Acad. Sci. USAHome page
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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J. Biol. Chem.Home page
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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CirculationHome page
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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Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
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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Am. J. Physiol. Endocrinol. Metab.Home page
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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Circ. Res.Home page
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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Endocr. Rev.Home page
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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FASEB J.Home page
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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Mol. Endocrinol.Home page
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]