doi: 10.1161/CIRCULATIONAHA.106.658260
(Circulation. 2006;114:2203-2205.)
© 2006 American Heart Association, Inc.
Editorial |
Increasing Evidence That Estrogen Is an Important Modulator of Bone Marrow–Mediated Cardiac Repair After Acute Infarction
From the Institute of Molecular Cardiology, University of Louisville, Louisville, Ky.
Correspondence to Roberto Bolli, MD, Division of Cardiology, University of Louisville, Louisville, KY 40292. E-mail rbolli{at}louisville.edu
Key Words: Editorials • estrogen receptors • myocardial infarction • bone marrow • stem cells
Extensive experimental and clinical evidence accumulated over the past several years indicates that the infarcted heart can be repaired by endogenous as well as exogenous stem/progenitor cells. Experimental studies from several laboratories have reported that bone marrow–derived endothelial progenitor cells (EPCs) are mobilized after acute myocardial infarction (MI), home to the infarcted myocardium, and improve left ventricular (LV) perfusion and function.1 Although EPCs have been shown to differentiate into a cardiomyocytic phenotype in vitro, EPC-induced beneficial effects appear to stem primarily from myocardial neovascularization. In an effort to enhance EPC-mediated cardiovascular reparative benefits, current studies are focused on the molecular mechanistic aspects of this phenomenon and on the modulation of EPC kinetics.
Article p 2261
Clinical evidence also supports an important role for EPCs in atherosclerotic cardiovascular disease. Lower numbers of colony-forming circulating EPCs are associated with an increased Framingham risk factor score and endothelial dysfunction,2 and the number of circulating EPCs predicts the severity of coronary artery disease.3 These observations underscore the fact that EPCs participate not only in tissue repair after injury but also in the maintenance of endothelial integrity and function. After a stressful event such as acute MI or myocardial ischemia, additional EPCs are mobilized from the bone marrow, home to the injured tissue, and participate in neovascularization. Taken together, these considerations suggest that enhanced cardiac repair after MI may potentially be achieved by augmenting mobilization, myocardial homing, and functionality of EPCs. Elucidation of the signaling mechanisms involved in these processes is therefore important to the development of therapeutic strategies for cardiac repair.
Although the role of EPCs in cardiac repair is a relatively new field of investigation, the influence of estrogen on cardiovascular health has been studied for decades. Estrogen exerts multifaceted effects on the heart and blood vessels via genomic and nongenomic actions. The genomic action is slower in onset and is mediated via 2 estrogen receptors (ERs), ER
and ERß. Both ER and ERß are expressed in endothelium, vascular smooth muscle cells, and cardiomyocytes. ERs are expressed primarily in the cytosol, and upon binding to estrogen (which diffuses into the cell), they translocate to the nucleus and regulate transcription of a number of genes. The tissue distribution of the 2 ERs varies considerably, and the effects of ERß-mediated signaling remain incompletely understood. Recent evidence indicates that estrogen augments production of EPCs4 and attenuates their senescence.5
In this issue of Circulation, Hamada and colleagues6 report a number of important new observations on the role of specific ERs in EPC biology and in cardiac repair. This report is a follow-up to a previous study7 in which these authors demonstrated that estradiol exerts cardioprotective effects in the setting of acute MI in mice via augmented mobilization and homing of EPCs and enhanced angiogenesis, resulting in improved cardiac function. The present findings identify a differential role of the 2 ERs in these phenomena. In vitro, the effects of estradiol on migration, proliferation, and tube formation by EPCs were severely impaired in EPCs from ER–/– mice, whereas they were moderately attenuated in EPCs from ERß–/– mice. In vivo, both the mobilization of endogenous Sca-1+/Flk-1+ EPCs after MI and the homing of exogenous EPCs to the infarct border zone after estradiol treatment were significantly greater in wild-type (WT) mice than those observed in WT recipients of ER–/– or ERß–/– marrow. Consistent with these findings, WT recipients of ER–/– or ERß–/– marrow exhibited lower capillary density in the border zone of the infarct and worse LV function. The absence of ER had a consistently greater impact on the end points of these experiments than did the absence of ERß. Furthermore, EPCs were found to express greater amounts of ER mRNA and bind estradiol in a predominantly ER-dependent manner. Interestingly, the expression of vascular endothelial growth factor in EPCs was significantly downregulated in the absence of ER. Taken together, the results of this elegant study indicate that, although both ERs participate in estradiol-induced cardiac repair via EPC mobilization, myocardial homing, and angiogenesis, signaling via ER is considerably more important in mediating these processes.
At present, the specific roles of ER and ERß in the cardiovascular system remain incompletely understood. Estradiol-induced reendothelialization in a mouse carotid artery injury model is ER dependent.8 Because EPCs contribute to reendothelialization after arterial injury, expression of ER on EPCs may be critical in this setting. In humans, women homozygous for the T allele of the PvuII polymorphism of ER are at greater risk of in-stent restenosis after coronary angioplasty.9 Furthermore, compared with the CT and TT genotypes, the CC genotype of ER is associated with an increased incidence of cardiovascular disease, including MI.10 Both observations9,10 support the primacy of ER in endothelial homeostasis. On the other hand, increased endothelial expression of ERß but not ER has been reported in a rat model of aortic balloon injury,11 and expression of ERß has been found to correlate with coronary calcification and atherosclerosis in pre- as well as postmenopausal women.12 In addition, after coronary artery ligation, ERß–/– mice have been reported to exhibit increased mortality and more severe heart failure despite similar infarct size compared with WT mice13; however, ER–/– mice were not examined. Thus, current evidence suggests that both ERs play important and possibly somewhat overlapping roles in the cardiovascular system. The findings of Hamada et al,6 which indicate greater expression of ER in EPCs and a greater role of ER in EPC-mediated repair of acute MI, are significant because they focus attention on this specific receptor. These results will likely stimulate further research into the relative contributions of ER vis-à-vis ERß to disease processes in which EPCs may potentially play a critical role, such as the genesis, progression, and repair of atherosclerotic lesions.
The reduction in the size of the scar observed in the present study after estradiol treatment is intriguing. Because cardiomyocytes express both ER and ERß, one could interpret these findings as evidence that estradiol exerted a direct cardioprotective effect (perhaps mediated by activation of the PI3-kinase-Akt pathway14) and limited the initial size of the infarct, resulting in subsequent smaller scars. This hypothesis, however, is not plausible because the authors used a model of permanent coronary occlusion. Myocytes rendered ischemic by a coronary occlusion cannot tolerate sustained severe ischemia; in the absence of reperfusion, no therapeutic intervention can salvage them, and these cells will die regardless of the treatment applied. Indeed, most previous studies showing that estradiol limits infarct size have used models of temporary coronary occlusion followed by reperfusion15–17; studies in models of permanent coronary ligation failed to show any infarct-sparing effect of estradiol.18,19 It appears far more likely that the reduced size of the scar observed by Hamada et al6 in estradiol-treated mice was due to attenuation of LV remodeling (producing less stretching of the scar), alleviation of the ongoing apoptosis of surviving myocytes after the acute phase of the infarct, regeneration of myocytes, and/or other as yet unknown processes. The mechanism that underlies the robust beneficial effects of estradiol on the size of the scar merits further investigation, for these studies may not only unravel novel aspects of ER biology but also illuminate new mechanisms whereby post-MI remodeling can be alleviated.
Another important issue that needs to be investigated is whether EPCs are the only bone marrow cell type that is modulated by ERs, or whether estrogen affects cardiac repair more broadly by regulating other bone marrow cells as well. The multifaceted effects of estrogen on bone marrow have been known for many years, and several types of bone marrow cells have been found to express ERs.20 In addition, besides EPCs, other bone marrow cells have been shown to express markers of endothelial lineage and, with appropriate stimuli and culture conditions, to differentiate into an endothelial phenotype.1 The role of ERs in modulating these potential candidates for neovascularization remains largely unknown. Furthermore, "circulating progenitors" with endothelial differentiation capability represent a phenotypically and functionally heterogeneous population.1,21 Hamada et al6 have recently shown that estradiol mobilizes EPCs via endothelial nitric oxide synthase–mediated activation of matrix metalloproteinase-9.7 Elucidation of the effects of estradiol on other bone marrow stem/progenitors could potentially identify other pathways by which estradiol affords reparative benefits in the cardiovascular system.
The findings of Hamada et al6 have significant clinical implications. First, ERß has been identified as the predominant ER isoform both in coronary intima and in coronary media in women.12 In view of the results of the population studies mentioned above, it seems important to investigate whether the number of circulating EPCs in subjects with ER variants correlates with the incidence of adverse cardiovascular events. If the findings of Hamada et al6 with regard to ER subtype expression in mouse EPCs hold true in humans, in vitro analysis of ER expression in EPCs may identify patients at greater risk of cardiovascular events. Second, given the beneficial effects of estradiol-induced mobilization of bone marrow cells on cardiac function, should estradiol be administered after acute MI, especially in postmenopausal women? The answer to this question appears to be rather complicated. Hormone replacement therapy (HRT) in postmenopausal women was the accepted standard of care for many years until a randomized clinical trial showed that HRT actually increased the risk of cardiac events.22 Several other studies have since reported either no benefit or deleterious effects of HRT on cardiovascular outcomes. In the specific setting of acute MI, however, there is evidence that HRT may improve mortality.23 The present results support this concept and suggest that, after acute MI, ER-specific therapies may be advantageous. A better understanding of estrogen signaling via specific ERs and future clinical studies with estrogen therapy alone may conceivably produce a therapeutic paradigm shift. Third, a growing body of evidence suggests that estrogen favorably modulates endothelial function after coronary stenting.24 If this beneficial effect is influenced by the ER expression pattern on human EPCs, selective ER modulators may be used to improve outcomes after stenting. Finally, premenopausal women appear to be protected from cardiovascular events. Because long-term estrogen exposure upregulates ER and downregulates ERß expression in endothelial cells,25 it will be interesting to determine whether gender-dependent differences in ER expression on EPCs (ie, greater expression of ER in women versus men) contribute to estrogen-related protection from cardiovascular events in premenopausal women.
In summary, despite numerous phenomenological reports, the role of circulating EPCs in endothelial and cardiac repair remains incompletely understood. The study by Hamada and colleagues6 is important because it reveals that, after MI, mobilization of EPCs, myocardial homing of these cells, and subsequent EPC-mediated cardiac repair are differentially regulated by specific ERs. These findings have clinical implications for understanding the relative roles of the 2 ERs in cardiovascular homeostasis and exploring the potential role of selective ER modulators in cardiac as well as vascular repair. Further studies will be necessary to investigate whether the ER-mediated beneficial effects of estradiol on postinfarction remodeling and function also involve other bone marrow cells, to decipher the molecular events whereby estradiol mobilizes EPCs, and to determine the mechanism whereby these EPCs home to the infarcted myocardium in an ER-dependent fashion.
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Acknowledgments |
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Sources of Funding
This publication was supported in part by NIH grants R01 HL-72410, HL-55757, HL-68088, HL-70897, HL-76794, and HL-78825.
Disclosures
None.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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References |
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 Top References |
|---|
- Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res. 2004; 95: 343–353.
[Abstract/Free Full Text] - Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003; 348: 593–600.
[Abstract/Free Full Text] - Kunz GA, Liang G, Cuculoski F, Gregg D, Vata KC, Shaw LK, Goldschmidt-Clermont PJ, Dong C, Taylor DA, Peterson ED. Circulating endothelial progenitor cells predict coronary artery disease severity. Am Heart J. 2006; 152: 190–195.[CrossRef][Medline]
[Order article via Infotrieve]
- Strehlow K, Werner N, Berweiler J, Link A, Dirnagl U, Priller J, Laufs K, Ghaeni L, Milosevic M, Bohm M, Nickenig G. Estrogen increases bone marrow–derived endothelial progenitor cell production and diminishes neointima formation. Circulation. 2003; 107: 3059–3065.
[Abstract/Free Full Text] - Imanishi T, Kobayashi K, Hano T, Nishio I. Effect of estrogen on differentiation and senescence in endothelial progenitor cells derived from bone marrow in spontaneously hypertensive rats. Hypertens Res. 2005; 28: 763–772.[CrossRef][Medline]
[Order article via Infotrieve]
- Hamada H, Kim MK, Iwakura A, Ii M, Thorne T, Qin G, Asai J, Tsutsumi Y, Sekiguchi H, Silver M, Wecker A, Bord E, Zhu Y, Kishore R, Losordo DW. Estrogen receptors and ß mediate contribution of bone marrow–derived endothelial progenitor cells to functional recovery after myocardial infarction. Circulation. 2006; 114: 2261–2270.
[Abstract/Free Full Text] - Iwakura A, Shastry S, Luedemann C, Hamada H, Kawamoto A, Kishore R, Zhu Y, Qin G, Silver M, Thorne T, Eaton L, Masuda H, Asahara T, Losordo DW. 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. 2006; 113: 1605–1614.
[Abstract/Free Full Text] - Brouchet L, Krust A, Dupont S, Chambon P, Bayard F, Arnal JF. Estradiol accelerates reendothelialization in mouse carotid artery through estrogen receptor-alpha but not estrogen receptor-beta. Circulation. 2001; 103: 423–428.
[Abstract/Free Full Text] - Ferrero V, Ribichini F, Matullo G, Guarrera S, Carturan S, Vado A, Vassanelli C, Piazza A, Uslenghi E, Wijns W. Estrogen receptor-alpha polymorphisms and angiographic outcome after coronary artery stenting. Arterioscler Thromb Vasc Biol. 2003; 23: 2223–2228.
[Abstract/Free Full Text] - Shearman AM, Cupples LA, Demissie S, Peter I, Schmid CH, Karas RH, Mendelsohn ME, Housman DE, Levy D. Association between estrogen receptor alpha gene variation and cardiovascular disease. JAMA. 2003; 290: 2263–2270.
[Abstract/Free Full Text] - Lindner V, Kim SK, Karas RH, Kuiper GG, Gustafsson JA, Mendelsohn ME. Increased expression of estrogen receptor-beta mRNA in male blood vessels after vascular injury. Circ Res. 1998; 83: 224–229.
[Abstract/Free Full Text] - Christian RC, Liu PY, Harrington S, Ruan M, Miller VM, Fitzpatrick LA. Intimal estrogen receptor (ER)beta, but not ERalpha expression, is correlated with coronary calcification and atherosclerosis in pre- and postmenopausal women. J Clin Endocrinol Metab. 2006; 91: 2713–2720.
[Abstract/Free Full Text] - Pelzer T, Loza PA, Hu K, Bayer B, Dienesch C, Calvillo L, Couse JF, Korach KS, Neyses L, Ertl G. Increased mortality and aggravation of heart failure in estrogen receptor-beta knockout mice after myocardial infarction. Circulation. 2005; 111: 1492–1498.
[Abstract/Free Full Text] - Patten RD, Pourati I, Aronovitz MJ, Baur J, Celestin F, Chen X, Michael A, Haq S, Nuedling S, Grohe C, Force T, Mendelsohn ME, Karas RH. 17beta-Estradiol reduces cardiomyocyte apoptosis in vivo and in vitro via activation of phospho-inositide-3 kinase/Akt signaling. Circ Res. 2004; 95: 692–699.
[Abstract/Free Full Text] - Hale SL, Birnbaum Y, Kloner RA. beta-Estradiol, but not alpha-estradiol, reduced myocardial necrosis in rabbits after ischemia and reperfusion. Am Heart J. 1996; 132: 258–262.[CrossRef][Medline]
[Order article via Infotrieve]
- Sbarouni E, Iliodromitis EK, Bofilis E, Kyriakides ZS, Kremastinos DT. Short-term estrogen reduces myocardial infarct size in oophorectomized female rabbits in a dose-dependent manner. Cardiovasc Drugs Ther. 1998; 12: 457–462.[CrossRef][Medline]
[Order article via Infotrieve]
- Booth EA, Marchesi M, Kilbourne EJ, Lucchesi BR. 17beta-Estradiol as a receptor-mediated cardioprotective agent. J Pharmacol Exp Ther. 2003; 307: 395–401.
[Abstract/Free Full Text] - Hugel S, Reincke M, Stromer H, Winning J, Horn M, Dienesch C, Mora P, Schmidt HH, Allolio B, Neubauer S. Evidence against a role of physiological concentrations of estrogen in post-myocardial infarction remodeling. J Am Coll Cardiol. 1999; 34: 1427–1434.
[Abstract/Free Full Text] - Smith PJ, Ornatsky O, Stewart DJ, Picard P, Dawood F, Wen WH, Liu PP, Webb DJ, Monge JC. Effects of estrogen replacement on infarct size, cardiac remodeling, and the endothelin system after myocardial infarction in ovariectomized rats. Circulation. 2000; 102: 2983–2989.
[Abstract/Free Full Text] - Zhou S, Zilberman Y, Wassermann K, Bain SD, Sadovsky Y, Gazit D. Estrogen modulates estrogen receptor alpha and beta expression, osteogenic activity, and apoptosis in mesenchymal stem cells (MSCs) of osteoporotic mice. J Cell Biochem. 2001; 81: 144–155.[CrossRef]
- Hur J, Yoon CH, Kim HS, Choi JH, Kang HJ, Hwang KK, Oh BH, Lee MM, Park YB. Characterization of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arterioscler Thromb Vasc Biol. 2004; 24: 288–293.
[Abstract/Free Full Text] - Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998; 280: 605–613.
[Abstract/Free Full Text] - Shlipak MG, Angeja BG, Go AS, Frederick PD, Canto JG, Grady D. Hormone therapy and in-hospital survival after myocardial infarction in postmenopausal women. Circulation. 2001; 104: 2300–2304.
[Abstract/Free Full Text] - Khan MA, Liu MW, Singh D, Pal A, Chio FL, Lawson D, Dean LS. Long-term (three years) effect of estrogen replacement therapy on major adverse cardiac events in postmenopausal women after intracoronary stenting. Am J Cardiol. 2000; 86: 330–333.[CrossRef][Medline]
[Order article via Infotrieve]
- Ihionkhan CE, Chambliss KL, Gibson LL, Hahner LD, Mendelsohn ME, Shaul PW. Estrogen causes dynamic alterations in endothelial estrogen receptor expression. Circ Res. 2002; 91: 814–820.
[Abstract/Free Full Text]
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