(Circulation. 1997;95:1505-1514.)
© 1997 American Heart Association, Inc.
Articles |
Estrogen-Receptor–Mediated Inhibition of Human Endothelial Cell Apoptosis
Estradiol as a Survival Factor
From the Department of Medicine, Division of Cardiovascular Research, St Elizabeth's Medical Center, Boston, Mass.
Correspondence to Douglas W. Losordo, MD, St Elizabeth's Medical Center, Department of Medicine, Division of Cardiovascular Research, 736 Cambridge St, Boston, MA 02135. E-mail dlosordo{at}opal.tufts.edu.
Background A series of studies was performed to examine the ability of estradiol (E2) to protect endothelial cells from apoptosis.
Methods and Results Light and transmission electron
microscopy demonstrated typical features of apoptosis in human
umbilical vein endothelial cells (HUVEC) exposed to tumor necrosis
factor-
(TNF-). Northern and Western blot analyses revealed
induction of message and protein for the interleukin-1ß converting
enzyme (ICE), which has been shown to mediate apoptosis induced by
TNF-. Immunofluorescent staining of HUVEC colocalized ICE expression
to apoptotic HUVEC. Direct cell counting demonstrated a significant
decrease in total endothelial cell number after 24 hours of TNF-
exposure and a dose-dependent reversal of the effect of TNF- with
E2 treatment. This protective effect was abrogated by an
estrogen-receptor antagonist. Fluorescence-activated cell sorting
analysis revealed 39.3% apoptosis after 24 hours of TNF- exposure.
Treatment with E2 resulted in a 50% decrease in apoptosis.
Similarly, viability assays revealed 35±4% cell death after TNF-
exposure. Simultaneous treatment with E2 resulted in a
dose-dependent reduction of cell death to a minimum of 18±2%. The
protective effect of E2 was nullified by a specific
estrogen-receptor antagonist.
Conclusions E2 treatment resulted in a
dose-dependent, receptor-mediated inhibition of TNF-–induced
endothelial cell apoptosis. These studies indicate that E2
may also serve a maintenance function in preventing endothelial cell
death after noxious stimuli and suggest that the ICE pathway may
mediate cytokine-induced apoptosis in endothelial cells. Preservation
of endothelial integrity represents another mechanism that may account
for the atheroprotective effect of estrogen.
Key Words: endothelium • hormones • estradiol • cells • receptors
This article has been cited by other articles:
 |
|
 |
|
  A. Maselli, P. Matarrese, E. Straface, S. Canu, F. Franconi, and W. Malorni Cell sex: a new look at cell fate studies FASEB J, April 1, 2009; 23(4): 978 - 984. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Werner and G. Nickenig Sex Hormones Save Our Skin: The Vascular Networking of Estrogen Circ. Res., January 30, 2009; 104(2): 135 - 137. [Full Text] [PDF]
|
|
|
|
|
|
C. E. Toutain, L. Brouchet, I. Raymond-Letron, P. Vicendo, H. Berges, J. Favre, M.-J. Fouque, A. Krust, A.-M. Schmitt, P. Chambon, et al. Prevention of Skin Flap Necrosis by Estradiol Involves Reperfusion of a Protected Vascular Network Circ. Res., January 30, 2009; 104(2): 245 - 254. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Lam Shang Leen, C. Filipe, A. Billon, B. Garmy-Susini, S. Jalvy, F. Robbesyn, D. Daret, C. Allieres, S. R. Rittling, N. Werner, et al. Estrogen-Stimulated Endothelial Repair Requires Osteopontin Arterioscler Thromb Vasc Biol, December 1, 2008; 28(12): 2131 - 2136. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Ishimaru, R. Arakaki, S. Yoshida, A. Yamada, S. Noji, and Y. Hayashi Expression of the retinoblastoma protein RbAp48 in exocrine glands leads to Sjogren's syndrome-like autoimmune exocrinopathy J. Exp. Med., November 24, 2008; 205(12): 2915 - 2927. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Yin, W.-W. Huang, C. Lin, H. Chen, A. MacKenzie, and L. Ma Estrogen Suppresses Uterine Epithelial Apoptosis by Inducing Birc1 Expression Mol. Endocrinol., January 1, 2008; 22(1): 113 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Kleinman, M. R. Greives, S. S. Churgin, K. M. Blechman, E. I. Chang, D. J. Ceradini, O. M. Tepper, and G. C. Gurtner Hypoxia-Induced Mediators of Stem/Progenitor Cell Trafficking Are Increased in Children With Hemangioma Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2664 - 2670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Masuda, C. Kalka, T. Takahashi, M. Yoshida, M. Wada, M. Kobori, R. Itoh, H. Iwaguro, M. Eguchi, Y. Iwami, et al. Estrogen-Mediated Endothelial Progenitor Cell Biology and Kinetics For Physiological Postnatal Vasculogenesis Circ. Res., September 14, 2007; 101(6): 598 - 606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. O'Lone, K. Knorr, I. Z. Jaffe, M. E. Schaffer, P. G. V. Martini, R. H. Karas, J. Bienkowska, M. E. Mendelsohn, and U. Hansen Estrogen Receptors {alpha} and {beta} Mediate Distinct Pathways of Vascular Gene Expression, Including Genes Involved in Mitochondrial Electron Transport and Generation of Reactive Oxygen Species Mol. Endocrinol., June 1, 2007; 21(6): 1281 - 1296. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Seli, O. Guzeloglu-Kayisli, H. Cakmak, U. A. Kayisli, B. Selam, and A. Arici Estradiol Increases Apoptosis in Human Coronary Artery Endothelial Cells by Up-Regulating Fas and Fas Ligand Expression J. Clin. Endocrinol. Metab., December 1, 2006; 91(12): 4995 - 5001. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zampino, M. Yuzhakova, J. Hansen, R. D. McKinney, P. H. Goldspink, D. L. Geenen, and P. M. Buttrick Sex-related dimorphic response of HIF-1{alpha} expression in myocardial ischemia Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H957 - H964. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Ishimaru, R. Arakaki, F. Omotehara, K. Yamada, K. Mishima, I. Saito, and Y. Hayashi Novel Role for RbAp48 in Tissue-Specific, Estrogen Deficiency-Dependent Apoptosis in the Exocrine Glands Mol. Cell. Biol., April 15, 2006; 26(8): 2924 - 2935. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M A J Herve, G Meduri, F G Petit, T S Domet, G Lazennec, S Mourah, and M Perrot-Applanat Regulation of the vascular endothelial growth factor (VEGF) receptor Flk-1/KDR by estradiol through VEGF in uterus J. Endocrinol., January 1, 2006; 188(1): 91 - 99. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. L. Ballard and J. M. Edelberg Harnessing Hormonal Signaling for Cardioprotection Sci. Aging Knowl. Environ., December 21, 2005; 2005(51): re6 - re6. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Takao, C. Kumagai, N. Hisakawa, R. Matsumoto, and K. Hashimoto Effect of 17{beta}-estradiol on tumor necrosis factor-{alpha}-induced cytotoxicity in the human peripheral T lymphocytes J. Endocrinol., January 1, 2005; 184(1): 191 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Dubey, E. K. Jackson, D. G. Gillespie, M. Rosselli, F. Barchiesi, A. Krust, H. Keller, L. C. Zacharia, and B. Imthurn Cytochromes 1A1/1B1- and Catechol-O-Methyltransferase-Derived Metabolites Mediate Estradiol-Induced Antimitogenesis in Human Cardiac Fibroblast J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 247 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zaitseva, D. S. Yue, J. A. Katzenellenbogen, P. A. W. Rogers, and C. E. Gargett Estrogen Receptor-{alpha} Agonists Promote Angiogenesis in Human Myometrial Microvascular Endothelial Cells Reproductive Sciences, December 1, 2004; 11(8): 529 - 535. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Mabuchi, M. Ohmichi, A. Kimura, Y. Nishio, E. Arimoto-Ishida, N. Yada-Hashimoto, K. Tasaka, and Y. Murata Estrogen Inhibits Paclitaxel-Induced Apoptosis via the Phosphorylation of Apoptosis Signal-Regulating Kinase 1 in Human Ovarian Cancer Cell Lines Endocrinology, January 1, 2004; 145(1): 49 - 58. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Iwakura, C. Luedemann, S. Shastry, A. Hanley, M. Kearney, R. Aikawa, J. M. Isner, T. Asahara, and D. W. Losordo Estrogen-Mediated, Endothelial Nitric Oxide Synthase-Dependent Mobilization of Bone Marrow-Derived Endothelial Progenitor Cells Contributes to Reendothelialization After Arterial Injury Circulation, December 23, 2003; 108(25): 3115 - 3121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Ishimaru, R. Arakaki, M. Watanabe, M. Kobayashi, K. Miyazaki, and Y. Hayashi Development of Autoimmune Exocrinopathy Resembling Sjogren's Syndrome in Estrogen-Deficient Mice of Healthy Background Am. J. Pathol., October 1, 2003; 163(4): 1481 - 1490. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Molloy, A. J. O'Neill, J. J. Grantham, M. Sheridan-Pereira, J. M. Fitzpatrick, D. W. Webb, and R. W. G. Watson Sex-specific alterations in neutrophil apoptosis: the role of estradiol and progesterone Blood, October 1, 2003; 102(7): 2653 - 2659. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
D. A. Goukassian, R. Kishore, K. Krasinski, C. Dolan, C. Luedemann, Y.-s. Yoon, M. Kearney, A. Hanley, H. Ma, T. Asahara, et al. Engineering the Response to Vascular Injury: Divergent Effects of Deregulated E2F1 Expression on Vascular Smooth Muscle Cells and Endothelial Cells Result in Endothelial Recovery and Inhibition of Neointimal Growth Circ. Res., July 25, 2003; 93(2): 162 - 169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Villablanca, K. A. Lewis, D. Tham, and J. C. Rutledge Differential regulation of gene expression by ovariectomy in mouse aorta Physiol Genomics, February 6, 2003; 12(3): 175 - 185. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Kishore, I. Spyridopoulos, C. Luedemann, and D. W. Losordo Functionally Novel Tumor Necrosis Factor-{alpha}-Modulated CHR-Binding Protein Mediates Cyclin A Transcriptional Repression in Vascular Endothelial Cells Circ. Res., August 23, 2002; 91(4): 307 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Spyridopoulos, C. Luedemann, D. Chen, M. Kearney, D. Chen, T. Murohara, N. Principe, J. M. Isner, and D. W. Losordo Divergence of Angiogenic and Vascular Permeability Signaling by VEGF: Inhibition of Protein Kinase C Suppresses VEGF-Induced Angiogenesis, but Promotes VEGF-Induced, NO-Dependent Vascular Permeability Arterioscler Thromb Vasc Biol, June 1, 2002; 22(6): 901 - 906. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Thompson, I. G. Sipes, B. D. Greenstein, and P. B. Hoyer 17{beta}-Estradiol Affords Protection against 4-Vinylcyclohexene Diepoxide-Induced Ovarian Follicle Loss in Fischer-344 Rats Endocrinology, March 1, 2002; 143(3): 1058 - 1065. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ling, A. Dai, M. R. I. Williams, K. Myles, R. J. Dilley, P. A. Komesaroff, and K. Sudhir Testosterone (T) Enhances Apoptosis-Related Damage in Human Vascular Endothelial Cells Endocrinology, March 1, 2002; 143(3): 1119 - 1125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Villablanca, K. A. Lewis, and J. C. Rutledge Time- and dose-dependent differential upregulation of three genes by 17beta -estradiol in endothelial cells J Appl Physiol, March 1, 2002; 92(3): 1064 - 1073. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. K. Dubey, S. Oparil, B. Imthurn, and E. K. Jackson Sex hormones and hypertension Cardiovasc Res, February 15, 2002; 53(3): 688 - 708. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Gruber, W. Tschugguel, C. Schneeberger, and J. C. Huber Production and Actions of Estrogens N. Engl. J. Med., January 31, 2002; 346(5): 340 - 352. [Full Text] [PDF]
|
|
|
|
|
|
C. Amant, P. Holm, S.-h. Xu, N. Tritman, M. Kearney, and D. W. Losordo Estrogen Receptor-Mediated, Nitric Oxide-Dependent Modulation of the Immunologic Barrier Function of the Endothelium: Regulation of Fas Ligand Expression by Estradiol Circulation, November 20, 2001; 104(21): 2576 - 2581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Chandrasekar, S. Nattel, and J.-F. Tanguay Coronary artery endothelial protection after local delivery of 17{beta}-estradiol during balloon angioplasty in a porcine model: a potential new pharmacologic approach to improve endothelial function J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1570 - 1576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Krasinski, I. Spyridopoulos, M. Kearney, and D. W. Losordo In Vivo Blockade of Tumor Necrosis Factor-{alpha} Accelerates Functional Endothelial Recovery After Balloon Angioplasty Circulation, October 9, 2001; 104(15): 1754 - 1756. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. H. WAGNER, M. R. SCHROETER, and M. HECKER 17{beta}-Estradiol inhibition of NADPH oxidase expression in human endothelial cells FASEB J, October 1, 2001; 15(12): 2121 - 2130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Mallat and A. Tedgui Current Perspective on the Role of Apoptosis in Atherothrombotic Disease Circ. Res., May 25, 2001; 88(10): 998 - 1003. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Spyridopoulos, P. Mayer, K. S. Shook, D. I. Axel, R. Viebahn, and K. R. Karsch Loss of cyclin A and G1-cell cycle arrest are a prerequisite of ceramide-induced toxicity in human arterial endothelial cells Cardiovasc Res, April 1, 2001; 50(1): 97 - 107. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Spyridopoulos, J. Wischhusen, B. Rabenstein, P. Mayer, D. I. Axel, K.-U. Frohlich, and K. R. Karsch Alcohol Enhances Oxysterol-Induced Apoptosis in Human Endothelial Cells by a Calcium-Dependent Mechanism Arterioscler Thromb Vasc Biol, March 1, 2001; 21(3): 439 - 444. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. K. Dubey and E. K. Jackson Estrogen-induced cardiorenal protection: potential cellular, biochemical, and molecular mechanisms Am J Physiol Renal Physiol, March 1, 2001; 280(3): F365 - F388. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Sudoh, K. Toba, M. Akishita, J. Ako, M. Hashimoto, K. Iijima, S. Kim, Y.-Q. Liang, Y. Ohike, T. Watanabe, et al. Estrogen Prevents Oxidative Stress-Induced Endothelial Cell Apoptosis in Rats Circulation, February 6, 2001; 103(5): 724 - 729. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Khastgir, J. Studd, N. Holland, J. Alaghband-Zadeh, S. Fox, and J. Chow Anabolic Effect of Estrogen Replacement on Bone in Postmenopausal Women with Osteoporosis: Histomorphometric Evidence in a Longitudinal Study J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 289 - 295. [Abstract] [Full Text]
|
|
|
|
|
|
P. Bausero, M.-H. Ben-Mahdi, J.-P. Mazucatelli, C. Bloy, and M. Perrot-Applanat Vascular endothelial growth factor is modulated in vascular muscle cells by estradiol, tamoxifen, and hypoxia Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2033 - H2042. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Dubey, E. K. Jackson, D. G. Gillespie, L. C. Zacharia, B. Imthurn, and P. J. Keller Clinically Used Estrogens Differentially Inhibit Human Aortic Smooth Muscle Cell Growth and Mitogen-Activated Protein Kinase Activity Arterioscler Thromb Vasc Biol, April 1, 2000; 20(4): 964 - 972. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sata, T. Suhara, and K. Walsh Vascular Endothelial Cells and Smooth Muscle Cells Differ in Expression of Fas and Fas Ligand and in Sensitivity to Fas Ligand-Induced Cell Death : Implications for Vascular Disease and Therapy Arterioscler Thromb Vasc Biol, February 1, 2000; 20(2): 309 - 316. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Walsh and J. M. Isner Apoptosis in inflammatory-fibroproliferative disorders of the vessel wall Cardiovasc Res, February 1, 2000; 45(3): 756 - 765. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 L. Jin, M. Qi, D.-Z. Chen, A. Anderson, G.-Y. Yang, J. M. Arbeit, and K. J. Auborn Indole-3-Carbinol Prevents Cervical Cancer in Human Papilloma Virus Type 16 (HPV16) Transgenic Mice Cancer Res., August 1, 1999; 59(16): 3991 - 3997. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Lund, J. Murdoch, E. A. Van Kirk, and W. J. Murdoch Mitogenic and Antioxidant Mechanisms of Estradiol Action in Preovulatory Ovine Follicles: Relevance to Luteal Function Biol Reprod, August 1, 1999; 61(2): 388 - 392. [Abstract] [Full Text]
|
|
|
|
|
|
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]
|
|
|
|
|
|
E. VEGETO, G. POLLIO, C. PELLICCIARI, and A. MAGGI Estrogen and progesterone induction of survival of monoblastoid cells undergoing TNF-{alpha}-induced apoptosis FASEB J, May 1, 1999; 13(8): 793 - 803. [Abstract] [Full Text]
|
|
|
|
|
|
D. Li, B. Yang, M. I. Philips, and J. L. Mehta Proapoptotic effects of ANG II in human coronary artery endothelial cells: role of AT1 receptor and PKC activation Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H786 - H792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Spyridopoulos, N. Principe, K. L. Krasinski, S.-h. Xu, M. Kearney, M. Magner, J. M. Isner, and D. W. Losordo Restoration of E2F Expression Rescues Vascular Endothelial Cells From Tumor Necrosis Factor-{alpha}–Induced Apoptosis Circulation, December 22, 1998; 98(25): 2883 - 2890. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Van Belle, C. Bauters, T. Asahara, and J. M. Isner Endothelial regrowth after arterial injury: from vascular repair to therapeutics Cardiovasc Res, April 1, 1998; 38(1): 54 - 68. [Full Text] [PDF]
|
|
|
|
|
|
J.-R. Nofer, B. Levkau, I. Wolinska, R. Junker, M. Fobker, A. von Eckardstein, U. Seedorf, and G. Assmann Suppression of Endothelial Cell Apoptosis by High Density Lipoproteins (HDL) and HDL-associated Lysosphingolipids J. Biol. Chem., September 7, 2001; 276(37): 34480 - 34485. [Abstract] [Full Text] [PDF]
|
|