(Circulation. 1996;94:727-733.)
© 1996 American Heart Association, Inc.
Articles |
Identification of Authentic Estrogen Receptor in Cultured Endothelial Cells
A Potential Mechanism for Steroid Hormone Regulation of Endothelial Function
the Cardiovascular Divisions (C.D.V., A.B.R., D.E.V.), Vanderbilt University Medical Center, and Nashville Veterans Affairs Medical Center (D.E.V.), Nashville, Tenn.
Correspondence to Douglas E. Vaughan, MD, Vanderbilt University Medical Center, Division of Cardiology, Rm 315 MRB II, Nashville, TN 37232-6300. E-mail Doug.Vaughan@mcmail.vanderbilt.edu.
Background Estrogen plays a major role in the delayed expression of coronary heart disease (CHD) in women, and recent data indicate that postmenopausal estrogen therapy reduces the incidence of CHD by >40%. The mechanism or mechanisms through which estrogen exerts this benefit are unknown, although effects on blood pressure, carbohydrate and lipid metabolism, and coagulation have been suggested. We hypothesized that at least part of the effect of estrogen in reducing the incidence of CHD is due to an effect on endothelial cell function.
Methods and Results In the present study, we examined human aortic and umbilical vein endothelial cells and bovine aortic endothelial cells for the presence of estrogen receptors (ERs) through immunoblot and mRNA analyses. Electrophoretic mobility shift assays were also performed to determine the DNA-binding properties of the putative ERs. Nuclear extracts from all three endothelial cell types were found to contain a 67-kD protein that reacted with anti-ER monoclonal antibodies specific to different domains of the ERs. Each of these types of cells expresses proteins that bind specifically to consensus estrogen-responsive elements. Finally, Northern blots verified that endothelial cells express abundant amount of mRNA for the ER.
Conclusions These data indicate that endothelial cells constitutively possess the potential for transcriptional regulation of target genes by estrogen. The evolutionary conservation of this receptor in bovine and human endothelial cells suggests a common mechanism for estrogen regulation of endothelial function.
Key Words: endothelium • hormones • receptors • coronary disease
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|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
C. S. Hayward, R. P. Kelly, and P. Collins The roles of gender, the menopause and hormone replacement on cardiovascular function Cardiovasc Res, April 1, 2000; 46(1): 28 - 49. [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
A. Huang, D. Sun, A. Koller, and G. Kaley 17{beta}-Estradiol Restores Endothelial Nitric Oxide Release to Shear Stress in Arterioles of Male Hypertensive Rats Circulation, January 4, 2000; 101(1): 94 - 100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 N. Charkoudian, D. P. Stephens, K. C. Pirkle, W. A. Kosiba, and J. M. Johnson Influence of female reproductive hormones on local thermal control of skin blood flow J Appl Physiol, November 1, 1999; 87(5): 1719 - 1723. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
E. Tan, M. V Gurjar, R. V Sharma, and R. C Bhalla Estrogen receptor-{alpha} gene transfer into bovine aortic endothelial cells induces eNOS gene expression and inhibits cell migration Cardiovasc Res, August 15, 1999; 43(3): 788 - 797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
M. E. Mendelsohn and R. H. Karas The Protective Effects of Estrogen on the Cardiovascular System N. Engl. J. Med., June 10, 1999; 340(23): 1801 - 1811. [Full Text] [PDF]
|
|
|
|
 |
|
 V. Zancan, S. Santagati, C. Bolego, E. Vegeto, A. Maggi, and L. Puglisi 17{beta}-Estradiol Decreases Nitric Oxide Synthase II Synthesis in Vascular Smooth Muscle Cells Endocrinology, May 1, 1999; 140(5): 2004 - 2009. [Abstract] [Full Text]
|
|
|
|
 |
|
 R. J. Gonzales and N. L. Kanagy Endothelium-Independent Relaxation of Vascular Smooth Muscle by 17{beta}-Estradiol Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1999; 4(4): 227 - 234. [Abstract] [PDF]
|
|
|
|
 |
|
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|
|
|
|
|
|
M. Christ and M. Wehling Cardiovascular steroid actions: swift swallows or sluggish snails? Cardiovasc Res, October 1, 1998; 40(1): 34 - 44. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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