on December 26, 2002
Arteriosclerosis, Thrombosis, and Vascular Biology. 2002
Published online before print December 26, 2002, doi: 10.1161/01.ATV.0000053846.71621.93
Published online before print December 26, 2002, doi: 10.1161/01.ATV.0000053846.71621.93
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on September 9, 2002
Accepted on October 24, 2002
Molecular Basis of Cell Membrane Estrogen Receptor Interaction With Phosphatidylinositol 3-Kinase in Endothelial Cells
Tommaso Simoncini *;
From the Cardiovascular Division, Department of Medicine (T.S., J.K.L.) and Department of Pathology (E.R.), Brigham & Women's Hospital and Harvard Medical School, Cambridge, Mass, and Molecular and Cellular Gynecological Endocrinology Laboratory (T.S.), Department of Reproductive Medicine and Child Development, University of Pisa, Italy.
* To whom correspondence should be addressed. E-mail: t.simoncini{at}obgyn.med.unipi.it.
Objective—Nontranscriptional signaling mechanisms mediate some of the biological effects of estrogen, such as the rapid actions on the blood vessels. By interacting with phosphatidylinositol 3-kinase (PI3K), estrogen receptor (ER) 
leads to activation of protein kinase Akt and to subsequent increase in endothelial nitric oxide synthase activity. Because PI3K is mainly a cytoplasmic complex, we studied the cellular site of interaction between this enzyme and ER, and we dissected the molecular mechanisms that mediate this interaction.
Methods and Results—By using cultured human saphenous vain endothelial cells, we found that cell membrane-bound ER colocalizes with PI3K and may be responsible for PI3K activation. Furthermore, we characterized the subsequent steps in the activation of the PI3K/Akt signaling cascade, comparing the molecular events that follow insulin or estradiol activation of PI3K.
Conclusions—We provide novel evidence for an important role of nonnuclear estrogen receptor in rapid, nontranscriptional responses of human endothelial cells to estrogen.
Key words: estrogen • estrogen receptor • nontranscriptional signaling • phosphatidylinositol 3-kinase • endothelium
This article has been cited by other articles:
 |
|
 |
|
  A. J. LeBlanc, R. Reyes, L. S. Kang, R. A. Dailey, J. N. Stallone, N. C. Moningka, and J. M. Muller-Delp Estrogen replacement restores flow-induced vasodilation in coronary arterioles of aged and ovariectomized rats Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2009; 297(6): R1713 - R1723. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Kazi, K. H. Molitoris, and R. D. Koos Estrogen Rapidly Activates the PI3K/AKT Pathway and Hypoxia-Inducible Factor 1 and Induces Vascular Endothelial Growth Factor A Expression in Luminal Epithelial Cells of the Rat Uterus Biol Reprod, August 1, 2009; 81(2): 378 - 387. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Gungor, I. Kalelioglu, and A. Turfanda Vascular Effects of Estrogen and Progestins and Risk of Coronary Artery Disease: Importance of Timing of Estrogen Treatment Angiology, June 1, 2009; 60(3): 308 - 317. [Abstract] [PDF]
|
|
|
|
 |
|
 B. Calippe, V. Douin-Echinard, M. Laffargue, H. Laurell, V. Rana-Poussine, B. Pipy, J.-C. Guery, F. Bayard, J.-F. Arnal, and P. Gourdy Chronic Estradiol Administration In Vivo Promotes the Proinflammatory Response of Macrophages to TLR4 Activation: Involvement of the Phosphatidylinositol 3-Kinase Pathway J. Immunol., June 15, 2008; 180(12): 7980 - 7988. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-Z. Sheng, F. Arshad, J. E. Braun, and A. P. Braun Estrogen and the Ca2+-mobilizing agonist ATP evoke acute NO synthesis via distinct pathways in an individual human vascular endothelium-derived cell Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1531 - C1541. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. D. Ullrich, A. Krust, P. Collins, and K. T. MacLeod Genomic deletion of estrogen receptors ER{alpha} and ER{beta} does not alter estrogen-mediated inhibition of Ca2+ influx and contraction in murine cardiomyocytes Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2421 - H2427. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Simoncini and A. R. Genazzani Dehydroepiandrosterone, the Endothelium, and Cardiovascular Protection Endocrinology, July 1, 2007; 148(7): 3065 - 3067. [Full Text] [PDF]
|
|
|
|
 |
|
 G. G. Leparc and R. D. Mitra Non-EST-based prediction of novel alternatively spliced cassette exons with cell signaling function in Caenorhabditis elegans and human Nucleic Acids Res., May 11, 2007; 35(10): 3192 - 3202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Kazi and R. D. Koos Estrogen-Induced Activation of Hypoxia-Inducible Factor-1{alpha}, Vascular Endothelial Growth Factor Expression, and Edema in the Uterus Are Mediated by the Phosphatidylinositol 3-Kinase/Akt Pathway Endocrinology, May 1, 2007; 148(5): 2363 - 2374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Simoncini, C. Scorticati, P. Mannella, A. Fadiel, M. S. Giretti, X.-D. Fu, C. Baldacci, S. Garibaldi, A. Caruso, L. Fornari, et al. Estrogen Receptor {alpha} Interacts with G{alpha}13 to Drive Actin Remodeling and Endothelial Cell Migration via the RhoA/Rho Kinase/Moesin Pathway Mol. Endocrinol., August 1, 2006; 20(8): 1756 - 1771. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Nakano, C.-J. Kwak, K. Fujii, K. Ikemura, A. Satake, M. Ohkita, M. Takaoka, Y. Ono, M. Nakai, N. Tomimori, et al. Sesamin Metabolites Induce an Endothelial Nitric Oxide-Dependent Vasorelaxation through Their Antioxidative Property-Independent Mechanisms: Possible Involvement of the Metabolites in the Antihypertensive Effect of Sesamin J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 328 - 335. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. R. Harrington, S. H. Kim, C. C. Funk, Z. Madak-Erdogan, R. Schiff, J. A. Katzenellenbogen, and B. S. Katzenellenbogen Estrogen Dendrimer Conjugates that Preferentially Activate Extranuclear, Nongenomic Versus Genomic Pathways of Estrogen Action Mol. Endocrinol., March 1, 2006; 20(3): 491 - 502. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. D. Norata, G. Tibolla, P. M. Seccomandi, A. Poletti, and A. L. Catapano Dihydrotestosterone Decreases Tumor Necrosis Factor-{alpha} and Lipopolysaccharide-Induced Inflammatory Response in Human Endothelial Cells J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 546 - 554. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Nagira, T. Sasaoka, T. Wada, K. Fukui, M. Ikubo, S. Hori, H. Tsuneki, S. Saito, and M. Kobayashi Altered Subcellular Distribution of Estrogen Receptor {alpha} Is Implicated in Estradiol-Induced Dual Regulation of Insulin Signaling in 3T3-L1 Adipocytes Endocrinology, February 1, 2006; 147(2): 1020 - 1028. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Schulz, E. Anter, M.-H. Zou, and J. F. Keaney Jr Estradiol-Mediated Endothelial Nitric Oxide Synthase Association With Heat Shock Protein 90 Requires Adenosine Monophosphate-Dependent Protein Kinase Circulation, June 28, 2005; 111(25): 3473 - 3480. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Chambliss, L. Simon, I. S. Yuhanna, C. Mineo, and P. W. Shaul Dissecting the Basis of Nongenomic Activation of Endothelial Nitric Oxide Synthase by Estradiol: Role of ER{alpha} Domains with Known Nuclear Functions Mol. Endocrinol., February 1, 2005; 19(2): 277 - 289. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Stirone, A. Boroujerdi, S. P. Duckles, and D. N. Krause Estrogen Receptor Activation of Phosphoinositide-3 Kinase, Akt, and Nitric Oxide Signaling in Cerebral Blood Vessels: Rapid and Long-Term Effects Mol. Pharmacol., January 1, 2005; 67(1): 105 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Liu, L. L. Homan, and J. S. Dillon Genistein Acutely Stimulates Nitric Oxide Synthesis in Vascular Endothelial Cells by a Cyclic Adenosine 5'-Monophosphate-Dependent Mechanism Endocrinology, December 1, 2004; 145(12): 5532 - 5539. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Simoncini, P. Mannella, L. Fornari, A. Caruso, M. Y. Willis, S. Garibaldi, C. Baldacci, and A. R. Genazzani Differential Signal Transduction of Progesterone and Medroxyprogesterone Acetate in Human Endothelial Cells Endocrinology, December 1, 2004; 145(12): 5745 - 5756. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Simoncini, P. Mannella, L. Fornari, A. Caruso, G. Varone, S. Garibaldi, and A. R. Genazzani Tibolone Activates Nitric Oxide Synthesis in Human Endothelial Cells J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4594 - 4600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Head, V. R. Obeyesekere, M. E. Jones, E. R. Simpson, and Z. S. Krozowski Aromatase-Deficient (ArKO) Mice Have Reduced Blood Pressure and Baroreflex Sensitivity Endocrinology, September 1, 2004; 145(9): 4286 - 4291. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. X. Song, C. J. Barnes, Z. Zhang, Y. Bao, R. Kumar, and R. J. Santen The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor {alpha} to the plasma membrane PNAS, February 17, 2004; 101(7): 2076 - 2081. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Huang, D. Sun, Z. Wu, C. Yan, M. A. Carroll, H. Jiang, J. R. Falck, and G. Kaley Estrogen Elicits Cytochrome P450--Mediated Flow-Induced Dilation of Arterioles in NO Deficiency: Role of PI3K-Akt Phosphorylation in Genomic Regulation Circ. Res., February 6, 2004; 94(2): 245 - 252. [Abstract] [Full Text] [PDF]
|
|