Circulation. 2003;107:3059-3065
Published online before print June 16, 2003, doi: 10.1161/01.CIR.0000077911.81151.30
Published online before print June 16, 2003, doi: 10.1161/01.CIR.0000077911.81151.30
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2003;107:3059.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Estrogen Increases Bone Marrow–Derived Endothelial Progenitor Cell Production and Diminishes Neointima Formation
From the Klinik und Poliklinik Innere Medizin III, Universität des Saarlandes (K.S., N.W., J.B., A.L., M.B., G.N.); the Klinik und Poliklinik für Neurologie, Charité, Humboldt-Universität zu Berlin (U.D., J.P., L.G., M.M.); and the Klinik und Poliklinik für Gynäkologie, Universität des Saarlandes (K.L.), Germany.
Correspondence to Dr Georg Nickenig, Klinik und Poliklinik Innere Medizin III, Universität des Saarlandes, 66421 Homburg/Saar, Germany. E-mail nickenig{at}med-in.uni-saarland.de
Background— Estrogens improve endothelial function and accelerate reendothelialization after vascular injury via largely unknown mechanisms. Bone marrow–derived endothelial progenitor cells (EPCs) are thought to positively influence endothelialization, vascular repair, and angiogenesis.
Methods and Results— In mice subjected to sham operation, ovariectomy, or ovariectomy and estrogen replacement treatment, estrogen deficiency significantly decreased EPCs circulating in the peripheral blood and residing in the bone marrow, as well as EPCs that were in vitro expanded from spleen-derived mononuclear cells. These effects were completely prevented by estrogen replacement. Human women with increased estrogen plasma concentrations also displayed profoundly increased levels of circulating EPCs. Estrogens increase EPC numbers through a decreased apoptosis rate, which is mediated via a caspase-8–dependent pathway. Estrogen deficiency increased neointima formation after carotid artery injury in mice, but this effect was diminished by estrogen replacement therapy. In mice transplanted with green fluorescent protein–positive bone marrow, reendothelialization of injured vessel segments by bone marrow–derived cells was decreased during estrogen deficiency and increased in response to estrogen treatment.
Conclusions— Estrogens increase numbers of EPCs by antiapoptotic effects leading to accelerated vascular repair and decreased neointima formation.
Key Words: arteriosclerosis • endothelium • restenosis • bone marrow • estrogen
This article has been cited by other articles:
 |
|
 |
|
  A. M. Leone, M. Valgimigli, M. B. Giannico, V. Zaccone, M. Perfetti, D. D'Amario, A. G. Rebuzzi, and F. Crea From bone marrow to the arterial wall: the ongoing tale of endothelial progenitor cells Eur. Heart J., April 2, 2009; 30(8): 890 - 899. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Stearns, V. G. Davila-Roman, B. Barzilai, R. E. Thompson, K. L. Grogan, B. Thomas, and C. W. Hogue Jr Prognostic Value of Troponin I Levels for Predicting Adverse Cardiovascular Outcomes in Postmenopausal Women Undergoing Cardiac Surgery Anesth. Analg., March 1, 2009; 108(3): 719 - 726. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-P. T Ruifrok, R. A de Boer, A. Iwakura, M. Silver, K. Kusano, R. A Tio, and D. W Losordo Estradiol-induced, endothelial progenitor cell-mediated neovascularization in male mice with hind-limb ischemia Vascular Medicine, February 1, 2009; 14(1): 29 - 36. [Abstract] [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]
|
|
|
|
|
|
S. Dimmeler and A. Leri Aging and Disease as Modifiers of Efficacy of Cell Therapy Circ. Res., June 6, 2008; 102(11): 1319 - 1330. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. C Villar, A. J Hobbs, and A. Ahluwalia Sex differences in vascular function: implication of endothelium-derived hyperpolarizing factor J. Endocrinol., June 1, 2008; 197(3): 447 - 462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. M. Miller and S. P. Duckles Vascular Actions of Estrogens: Functional Implications Pharmacol. Rev., June 1, 2008; 60(2): 210 - 241. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Filipe, L. Lam Shang Leen, L. Brouchet, A. Billon, V. Benouaich, V. Fontaine, P. Gourdy, F. Lenfant, J.-F. Arnal, A.-P. Gadeau, et al. Estradiol accelerates endothelial healing through the retrograde commitment of uninjured endothelium Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2822 - H2830. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. P. Fadini, S. de Kreutzenberg, M. Albiero, A. Coracina, E. Pagnin, I. Baesso, A. Cignarella, C. Bolego, M. Plebani, G. B. Nardelli, et al. Gender Differences in Endothelial Progenitor Cells and Cardiovascular Risk Profile: The Role of Female Estrogens Arterioscler. Thromb. Vasc. Biol., May 1, 2008; 28(5): 997 - 1004. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Ray, C. M. Herring, T. A. Markel, P. R. Crisostomo, M. Wang, B. Weil, T. Lahm, and D. R. Meldrum Deleterious effects of endogenous and exogenous testosterone on mesenchymal stem cell VEGF production Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2008; 294(5): R1498 - R1503. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Foteinos, Y. Hu, Q. Xiao, B. Metzler, and Q. Xu Rapid Endothelial Turnover in Atherosclerosis-Prone Areas Coincides With Stem Cell Repair in Apolipoprotein E-Deficient Mice Circulation, April 8, 2008; 117(14): 1856 - 1863. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Rienstra, C. J. Zeebregts, and J.-L. Hillebrands The Source of Neointimal Cells in Vein Grafts: Does the Origin Matter? Am. J. Pathol., March 1, 2008; 172(3): 566 - 570. [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]
|
|
|
|
 |
|
 C. Werner, C. H. Kamani, C. Gensch, M. Bohm, and U. Laufs The Peroxisome Proliferator Activated Receptor-{gamma} Agonist Pioglitazone Increases Number and Function of Endothelial Progenitor Cells in Patients With Coronary Artery Disease and Normal Glucose Tolerance Diabetes, October 1, 2007; 56(10): 2609 - 2615. [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]
|
|
|
|
 |
|
 Y. Wang, Y. Zheng, W. Zhang, H. Yu, K. Lou, Y. Zhang, Q. Qin, B. Zhao, Y. Yang, and R. Hui Polymorphisms of KDR Gene Are Associated With Coronary Heart Disease J. Am. Coll. Cardiol., August 21, 2007; 50(8): 760 - 767. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Rajasingh, E. Bord, G. Qin, M. Ii, M. Silver, H. Hamada, D. Ahluwalia, D. Goukassian, Y. Zhu, D. W. Losordo, et al. Enhanced Voluntary Alcohol Consumption after Estrogen Supplementation Negates Estrogen-Mediated Vascular Repair in Ovariectomized Mice Endocrinology, August 1, 2007; 148(8): 3618 - 3624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M Cubbon, A. Rajwani, and S. B Wheatcroft The impact of insulin resistance on endothelial function, progenitor cells and repair Diabetes and Vascular Disease Research, June 1, 2007; 4(2): 103 - 111. [Abstract] [PDF]
|
|
|
|
|
|
A. V. R. Santhanam, L. A. Smith, T. He, K. A. Nath, and Z. S. Katusic Endothelial Progenitor Cells Stimulate Cerebrovascular Production of Prostacyclin By Paracrine Activation of Cyclooxygenase-2 Circ. Res., May 11, 2007; 100(9): 1379 - 1388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. P. Fadini, S. Sartore, C. Agostini, and A. Avogaro Significance of Endothelial Progenitor Cells in Subjects With Diabetes Diabetes Care, May 1, 2007; 30(5): 1305 - 1313. [Full Text] [PDF]
|
|
|
|
|
|
V. L.T. Ballard and J. M. Edelberg Stem Cells and the Regeneration of the Aging Cardiovascular System Circ. Res., April 27, 2007; 100(8): 1116 - 1127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Dawn and R. Bolli Increasing Evidence That Estrogen Is an Important Modulator of Bone Marrow-Mediated Cardiac Repair After Acute Infarction Circulation, November 21, 2006; 114(21): 2203 - 2205. [Full Text] [PDF]
|
|
|
|
|
|
H. Hamada, M. K. Kim, A. Iwakura, M. Ii, T. Thorne, G. Qin, J. Asai, Y. Tsutsumi, H. Sekiguchi, M. Silver, et al. Estrogen Receptors {alpha} and {beta} Mediate Contribution of Bone Marrow-Derived Endothelial Progenitor Cells to Functional Recovery After Myocardial Infarction Circulation, November 21, 2006; 114(21): 2261 - 2270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Foresta, N. Caretta, A. Lana, L. De Toni, A. Biagioli, A. Ferlin, and A. Garolla Reduced Number of Circulating Endothelial Progenitor Cells in Hypogonadal Men J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4599 - 4602. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Fontaine, C. Filipe, N. Werner, P. Gourdy, A. Billon, B. Garmy-Susini, L. Brouchet, F. Bayard, H. Prats, T. Doetschman, et al. Essential Role of Bone Marrow Fibroblast Growth Factor-2 in the Effect of Estradiol on Reendothelialization and Endothelial Progenitor Cell Mobilization Am. J. Pathol., November 1, 2006; 169(5): 1855 - 1862. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Wassmann, N. Werner, T. Czech, and G. Nickenig Improvement of Endothelial Function by Systemic Transfusion of Vascular Progenitor Cells Circ. Res., October 13, 2006; 99(8): E74 - E83. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Xiao, L. Zeng, Z. Zhang, A. Margariti, Z. A Ali, K. M. Channon, Q. Xu, and Y. Hu Sca-1+ Progenitors Derived From Embryonic Stem Cells Differentiate Into Endothelial Cells Capable of Vascular Repair After Arterial Injury Arterioscler. Thromb. Vasc. Biol., October 1, 2006; 26(10): 2244 - 2251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Baumhakel, N. Werner, M. Bohm, and G. Nickenig Circulating endothelial progenitor cells correlate with erectile function in patients with coronary heart disease Eur. Heart J., September 2, 2006; 27(18): 2184 - 2188. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Bushnell, P. Hurn, C. Colton, V. M. Miller, G. del Zoppo, M. S.V. Elkind, B. Stern, D. Herrington, G. Ford-Lynch, P. Gorelick, et al. Advancing the Study of Stroke in Women: Summary and Recommendations for Future Research From an NINDS-Sponsored Multidisciplinary Working Group Stroke, September 1, 2006; 37(9): 2387 - 2399. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. X. Ma, B. Zhou, Z. Chen, Q. Ren, S. H. Lu, T. Sawamura, and Z. C. Han Oxidized low density lipoprotein impairs endothelial progenitor cells by regulation of endothelial nitric oxide synthase J. Lipid Res., June 1, 2006; 47(6): 1227 - 1237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Nakano, Y. Adachi, K. Minamino, M. Iwasaki, A. Shigematsu, N. Kiriyama, Y. Suzuki, Y. Koike, H. Mukaide, S. Taniuchi, et al. Mechanisms Underlying Acceleration of Blood Flow Recovery in Ischemic Limbs by Macrophage Colony-Stimulating Factor Stem Cells, May 1, 2006; 24(5): 1274 - 1279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Iwakura, S. Shastry, C. Luedemann, H. Hamada, A. Kawamoto, R. Kishore, Y. Zhu, G. Qin, M. Silver, T. Thorne, et al. Estradiol Enhances Recovery After Myocardial Infarction by Augmenting Incorporation of Bone Marrow-Derived Endothelial Progenitor Cells Into Sites of Ischemia-Induced Neovascularization via Endothelial Nitric Oxide Synthase-Mediated Activation of Matrix Metalloproteinase-9 Circulation, March 28, 2006; 113(12): 1605 - 1614. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ii, H. Takenaka, J. Asai, K. Ibusuki, Y. Mizukami, K. Maruyama, Y.-s. Yoon, A. Wecker, C. Luedemann, E. Eaton, et al. Endothelial Progenitor Thrombospondin-1 Mediates Diabetes-Induced Delay in Reendothelialization Following Arterial Injury Circ. Res., March 17, 2006; 98(5): 697 - 704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Langer, A. E. May, K. Daub, U. Heinzmann, P. Lang, M. Schumm, D. Vestweber, S. Massberg, T. Schonberger, I. Pfisterer, et al. Adherent Platelets Recruit and Induce Differentiation of Murine Embryonic Endothelial Progenitor Cells to Mature Endothelial Cells In Vitro Circ. Res., February 3, 2006; 98(2): e2 - e10. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Werner and G. Nickenig Influence of Cardiovascular Risk Factors on Endothelial Progenitor Cells: Limitations for Therapy? Arterioscler. Thromb. Vasc. Biol., February 1, 2006; 26(2): 257 - 266. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Gimenez, P. M Garcia, B. Bonacasa, L. F Carbonell, T. Quesada, and I. Hernandez Effects of oestrogen treatment and angiotensin-converting enzyme inhibition on the microvasculature of ovariectomized spontaneously hypertensive rats Exp Physiol, January 1, 2006; 91(1): 261 - 268. [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]
|
|
|
|
 |
|
 E. L. Burnham, W. R. Taylor, A. A. Quyyumi, M. Rojas, K. L. Brigham, and M. Moss Increased Circulating Endothelial Progenitor Cells Are Associated with Survival in Acute Lung Injury Am. J. Respir. Crit. Care Med., October 1, 2005; 172(7): 854 - 860. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Werner, S. Kosiol, T. Schiegl, P. Ahlers, K. Walenta, A. Link, M. Bohm, and G. Nickenig Circulating Endothelial Progenitor Cells and Cardiovascular Outcomes N. Engl. J. Med., September 8, 2005; 353(10): 999 - 1007. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Md. R. Abid, K. Yano, S. Guo, V. I. Patel, G. Shrikhande, K. C. Spokes, C. Ferran, and W. C. Aird Forkhead Transcription Factors Inhibit Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia J. Biol. Chem., August 19, 2005; 280(33): 29864 - 29873. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. J. Dzau, M. Gnecchi, A. S. Pachori, F. Morello, and L. G. Melo Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases Hypertension, July 1, 2005; 46(1): 7 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kravchenko, P. J. Goldschmidt-Clermont, T. Powell, E. Stallard, I. Akushevich, M. S. Cuffe, and K. G. Manton Endothelial Progenitor Cell Therapy for Atherosclerosis: The Philosopher's Stone for an Aging Population? Sci. Aging Knowl. Environ., June 22, 2005; 2005(25): pe18 - pe18. [Abstract] [Full Text]
|
|
|
|
|
|
C. Dong, L. E. Crawford, and P. J. Goldschmidt-Clermont Endothelial Progenitor Obsolescence and Atherosclerotic Inflammation J. Am. Coll. Cardiol., May 3, 2005; 45(9): 1458 - 1460. [Full Text] [PDF]
|
|
|
|
|
|
A. Aicher, A. M. Zeiher, and S. Dimmeler Mobilizing Endothelial Progenitor Cells Hypertension, March 1, 2005; 45(3): 321 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yamamoto, T. Kondo, S. Suzuki, H. Izawa, M. Kobayashi, N. Emi, K. Komori, T. Naoe, J. Takamatsu, and T. Murohara Molecular Evaluation of Endothelial Progenitor Cells in Patients With Ischemic Limbs: Therapeutic Effect by Stem Cell Transplantation Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): e192 - e196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Abedin, Y. Tintut, and L. L. Demer Mesenchymal Stem Cells and the Artery Wall Circ. Res., October 1, 2004; 95(7): 671 - 676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. Melo, M. Gnecchi, A. S. Pachori, D. Kong, K. Wang, X. Liu, R. E. Pratt, and V. J. Dzau Endothelium-Targeted Gene and Cell-Based Therapies for Cardiovascular Disease Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1761 - 1774. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. He, L. A. Smith, S. Harrington, K. A. Nath, N. M. Caplice, and Z. S. Katusic Transplantation of Circulating Endothelial Progenitor Cells Restores Endothelial Function of Denuded Rabbit Carotid Arteries Stroke, October 1, 2004; 35(10): 2378 - 2384. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L.G Melo, M Gnecchi, A.S Pachori, K Wang, and V.J Dzau Gene- and cell-based therapies for cardiovascular diseases: current status and future directions Eur. Heart J. Suppl., September 1, 2004; 6(suppl_E): E24 - E35. [Abstract] [Full Text]
|
|
|
|
|
|
C. Urbich and S. Dimmeler Endothelial Progenitor Cells: Characterization and Role in Vascular Biology Circ. Res., August 20, 2004; 95(4): 343 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-H. Choi, K. L. Kim, W. Huh, B. Kim, J. Byun, W. Suh, J. Sung, E.-S. Jeon, H.-Y. Oh, and D.-K. Kim Decreased Number and Impaired Angiogenic Function of Endothelial Progenitor Cells in Patients With Chronic Renal Failure Arterioscler. Thromb. Vasc. Biol., July 1, 2004; 24(7): 1246 - 1252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Verma, M. A. Kuliszewski, S.-H. Li, P. E. Szmitko, L. Zucco, C.-H. Wang, M. V. Badiwala, D. A.G. Mickle, R. D. Weisel, P. W.M. Fedak, et al. C-Reactive Protein Attenuates Endothelial Progenitor Cell Survival, Differentiation, and Function: Further Evidence of a Mechanistic Link Between C-Reactive Protein and Cardiovascular Disease Circulation, May 4, 2004; 109(17): 2058 - 2067. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Laufs, N. Werner, A. Link, M. Endres, S. Wassmann, K. Jurgens, E. Miche, M. Bohm, and G. Nickenig Physical Training Increases Endothelial Progenitor Cells, Inhibits Neointima Formation, and Enhances Angiogenesis Circulation, January 20, 2004; 109(2): 220 - 226. [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]
|
|
|
|
|
|
S. Dimmeler and M. Vasa-Nicotera Aging of progenitor cells: limitation for regenerative capacity? J. Am. Coll. Cardiol., December 17, 2003; 42(12): 2081 - 2082. [Full Text] [PDF]
|
|