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A novel hypothesis of atherosclerosis: EPCs-mediated repair-to-injury
Medical Hypotheses (2008) 70, 838–841
http://intl.elsevierhealth.com/journals/mehy
A novel hypothesis of atherosclerosis: EPCs-mediated repair-to-injury Ming Zhang, Sheng-hua Zhou *, Xu-ping Li, Xiang-Qian Shen, Zhen-fei Fang Department of Cardiology, Second Xiangya Hospital, Central South University, Changsha Hunan 410011, China Received 21 June 2007; accepted 24 June 2007
Summary Recent findings demonstrate the vital role of endothelial progenitor cells in the homeostasis of the vessel wall and the development of atherosclerosis. Endothelial progenitor cells (EPCs) play important roles in repair-toinjury of arteries. Many evidences have shown Cardiovascular risk factors closely correlated with EPCs numbers and function. Levels of circulating EPCs represented a better predictor of endothelial function than conventional risk factors. Depletion of bone marrow and Cardiovascular risk factors are the two prerequisits of atherosclerosis. All conditions of manifest atherosclerotic disease are accompanied by reduced EPC numbers and migratory capacity. Therefore, based on response-to-injury hypothesis and these findings, we build up EPCs-mediated repair-to-injury hypothesis, which may have important therapeutic implications in the prevention and therapy of atherosclerosis. The use of EPCs for vascular repair may be important therapy strategies with a maximized benefit for the patient in the future. c 2007 Elsevier Ltd. All rights reserved.
Introduction Atherosclerosis is the leading cause of death in the world and is an inflammatory process that selectively affects arteries and is highly prevalent in both women and men. Thrombo-occlusive complications of atherosclerosis, including stroke and myocardial infarction, are major causes of morbidity and mortality. Despite intense research efforts, the underlying molecular mechanisms of atherosclerosis are still incompletely understood, how-
* Corresponding author. Tel.: +86 731 5292013. E-mail address: [email protected] (S.-h. Zhou).
ever, many findings have demonstrated the vital role of progenitor cells in the homeostasis of the vessel wall and the mitigation of atherosclerosis. Therefore, based on response-to-injury hypothesis of atherosclerosis, we set up EPC-mediated repair-to-injury hypothesis.
The risk factors of atherosclerosis closely correlated with EPCs numbers and function A growing body of evidence suggests that circulating EPCs play an important role in endothelial cell
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.06.041
A novel hypothesis of atherosclerosis
839
regeneration. Small clinical studies have shown that the number of circulating EPCs inversely correlates with risk factors for atherosclerosis [1,2]. Hill et al. demonstrated a strong correlation between the number of circulating EPCs and the patient’s combined Framingham risk factor score [1]. Cardiovascular risk factors have been closely associated with reduced EPCs numbers and function. All conditions of manifest atherosclerotic disease are accompanied by reduced EPC numbers and migratory capacity [2]. Circulating CD34/KDR-positive progenitor cells are reduced in patients with coronary artery disease (CAD). In addition, EPCs isolated from patients with CAD displayed an impaired migratory response, which was inversely correlated with the number of cardiovascular risk factors [3–5]. Vasculoprotective agents increase the number and function of endothelial progenitor cells improving endothelial function and preventing progression of atherosclerosis. Human studies clearly demonstrate that high EPC levels are associated with reduced cardiovascular event rates underlining the vasculoprotective action of EPCs [6,7]. All major known cardiovascular risk factors negatively influence number of EPCs, migratory capacity, as well as the clonogenic potential of progenitor cells.
erosclerosis, it can lead to reduced flow as a result of narrowing of the lumen and consequent ischemia for downstream tissues. The pathological remodeling usually result in acute coronary syndromes, even acute myocardial infarction these disease frequently go along with elevated numbers of EPCs, which also indicating that EPC-mediated tissue and vessel repair is a ‘‘physiological’’ response of the organism after severe ischemia, simultaneously, the mobilized EPCs are functionally impaired [12–14]. Local injury of the arterial wall also triggers a powerful recruitment of vascular cells, either through in situ proliferation or by engraftment of bone marrow – derived progenitor cells [15,16]. This process of repair can be misguided and contribute to vascular lesion progression [17,18]. As a general rule, the repair is rapid and successful and the inflammatory reaction are self-limited [19], however, Failure to repair the arterial wall in response to inflammatory signals will further promote atherogenesis and hence create a positive feedback loop that propagates vessel injury.
The crucial roles of progenitor cells in repair-to-injury process
In the presence of competent bone marrow, the repair to injury of arterial always can be successful or self-limited.The inflammatory reaction is self-contained because the repair of the arterial wall results in the discontinuation of the stimulus that had triggered the inflammatory reaction. In contrast, in the absence of competent marrow, an arterial lesion has no opportunity to become repaired, and this lack of repair contributes to perpetuating and even intensifying of the atherosclerotic inflammation, with progressive senescence and dysfunctional remodeling of the arterial wall. Most likely, the observed impairment of progenitor cells in these patients is attributable to the accumulation of cardiovascular risk factors resulting in a reduced regenerative potential [2]. Cardiovascular risk factors, especially Aging, can lead to depletion of bone marrow cells capable of repair of the arterial wall [20–22]. Indeed, the depletion of bone marrow–derived progenitor cells may account for a large fraction of the aging risk in the development of vascular disorders [22]. Such depletion of competent cells may involve the loss of production of progenitors by a dysfunctional marrow or the marrow production of dysfunctional progenitor cells that are therefore incapable of
Various studies have underlined the important role of bone marrow–derived endothelial progenitor cells (EPCs) in vasculogenesis and angiogenesis of ischemic tissue. All conditions of manifest atherosclerotic disease are accompanied by reduced EPC numbers and migratory capacity [2]. Most likely, the observed impairment of progenitor cells in these patients is attributable to the accumulation of cardiovascular risk factors resulting in a reduced regenerative potential. According to the response-to-injury hypothesis, cardiovascular risk factors induce a chemical or mechanical injury of the endothelium that triggers and finally results in endothelial dysfunction [8]. The latter is a prerequisite of atherosclerosis [9–11]. The injured arterial wall mounts a profound systemic response that involves a cascade of molecular and cellular events to promote the repair of the vessel wall.The repair and remodeling of the arterial wall are regulated by circulation of progenitor cells by the bone marrow and other organs. Many evidences have shown EPCs plays a crucial roles in this process of repair and remodeling.When remodeling becomes pathological, especially in advanced ath-
Prerequisites of atherosclerosis: Cardiovascular risk factors and depletion of bone marrow
840 repair [22]. Competent progenitors might also be produced but may not be released by the marrow. It is still possible that repair-competent progenitor cells are produced and circulate but are unable to latch onto arterial lesions, once latched, these competent progenitor cells might be unable to mount a successful repair process as a result of local hemodynamic and other factors.
Clinical implications Strengthening the regenerative capacity of the organism seems one way to reduce the incidence of atherosclerosis. This may have important therapeutic implications, but only a few studies have concentrated on the role of EPCs in the prevention and therapy of atherosclerosis. In the future, the use of EPCs for vascular repair may be important for choosing therapy strategies with a maximized benefit for the patient. This implicates that improvement of number and function of EPCs may result in an effective vasculoprotection preventing the initiation and progression of atherosclerosis. There is good evidence that statins and ACE inhibitor mediate at least part of their pleiotrophic, vasculoprotective action via EPCs. In addition, physical activity and estrogens have been shown to influence EPC number and function [23]. Experimental data demonstrate that systemic transfusion of healthy EPCs in conditions of arterial EC denudation can enhance re-endothelialization, resulting in a diminished neointima formation. Furthermore, transfusion of healthy EPCs derived from wild-type mice in apolipoprotein E knockout mice can improve hypercholesterolemia-induced endothelial dysfunction and the development of atherosclerosis [24]. These results suggest that EPCs are equipped with efficient protection systems, making these cells even more attractive for cell therapy.These topics represent exciting future areas of investigation and might have a profound impact on our understanding of vascular disease and repair.
References [1] Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003;348:593–600. [2] Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 2001;89: E1–7.
Zhang et al. [3] Chen JZ, Zhu JH, Wang XX, Zhu JH, Xie XD, Sun J, et al. Effects of homocysteine on number and activity of endothelial progenitor cells from peripheral blood. J Mol Cell Cardiol 2004;36:233–9. [4] Suh W, Kim KL, Choi JH, Lee YS, Lee JY, Kim JM, et al. Creactive protein impairs angiogenic functions and decreases the secretion of arteriogenic chemo-cytokines in human endothelial progenitor cells. Biochem Biophys Res Commun 2004;321:65–71. [5] Verma S, Kuliszewski MA, Li SH, Szmitko PE, Zucco L, Wang CH, 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 2004;109:2058–67. [6] Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 2005;353:999–1007. [7] Schmidt-Lucke C, Rossig L, Fichtlscherer S, Vasa M, Britten M, Kamper U, et al. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation 2005;111:2981–7. [8] Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999;340:115–26. [9] Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 2001;104:2673–8. [10] Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000;101:1899–906. [11] Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes Jr DR, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000;101:948–54. [12] Goldschmidt-Clermont PJ, Kandzari DE, Sketch Jr MH, Phillips HR. Inflammation, platelets, and glycoprotein IIb/ IIIa inhibitors. J Invasive Cardiol 2002;14(suppl E):18E–26E. [13] Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-, in vivo. J Clin Endocrinol Metab 1997;82:4196–200. [14] Goldschmidt-Clermont PJ. Loss of bone marrow – derived vascular progenitor cells leads to inflammation and atherosclerosis. Am Heart J 2003;146(suppl):S5–S12. [15] Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964–7. [16] Lin Y, Weisdorf DJ, Solovey A, Hebbel RP. Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest 2000;105:71–7. [17] Shi W, Haberland ME, Jien ML, Shih DM, Lusis AJ. Endothelial responses to oxidized lipoproteins determine genetic susceptibility to atherosclerosis in mice. Circulation 2000;102:75–81. [18] Epstein SE. The multiple mechanisms by which infection may contribute to atherosclerosis development and course. Circ Res 2002;90:2–4. [19] Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, Wang T, Gregg D, Ramaswami P, et al. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation 2003;108:457–63. [20] Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, Wang T, Gregg D, Ramaswami P, et al. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation 2003;108: 457–63.
A novel hypothesis of atherosclerosis [21] Sata M, Saiura A, Kunisato A, Tojo A, Okada S, Tokuhisa T, et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 2002;8:403–9. [22] Goldschmidt-Clermont PJ, Peterson ED. On the memory of a chronic illness. Sci Aging Knowl Environ 2003;2003:re8.
841 [23] Nikos Werner. Georg Nickenig influence of cardiovascular risk factors on endothelial progenitor cells. Arterioscl Throm Vas Biol 2006;26:257. [24] Goldschmidt-Clermont PJ. Loss of bone marrow – derived vascular progenitor cells leads to inflammation and atherosclerosis. Am Heart J 2003;146(suppl):S5–S12.
http://intl.elsevierhealth.com/journals/mehy
A novel hypothesis of atherosclerosis: EPCs-mediated repair-to-injury Ming Zhang, Sheng-hua Zhou *, Xu-ping Li, Xiang-Qian Shen, Zhen-fei Fang Department of Cardiology, Second Xiangya Hospital, Central South University, Changsha Hunan 410011, China Received 21 June 2007; accepted 24 June 2007
Summary Recent findings demonstrate the vital role of endothelial progenitor cells in the homeostasis of the vessel wall and the development of atherosclerosis. Endothelial progenitor cells (EPCs) play important roles in repair-toinjury of arteries. Many evidences have shown Cardiovascular risk factors closely correlated with EPCs numbers and function. Levels of circulating EPCs represented a better predictor of endothelial function than conventional risk factors. Depletion of bone marrow and Cardiovascular risk factors are the two prerequisits of atherosclerosis. All conditions of manifest atherosclerotic disease are accompanied by reduced EPC numbers and migratory capacity. Therefore, based on response-to-injury hypothesis and these findings, we build up EPCs-mediated repair-to-injury hypothesis, which may have important therapeutic implications in the prevention and therapy of atherosclerosis. The use of EPCs for vascular repair may be important therapy strategies with a maximized benefit for the patient in the future. c 2007 Elsevier Ltd. All rights reserved.
Introduction Atherosclerosis is the leading cause of death in the world and is an inflammatory process that selectively affects arteries and is highly prevalent in both women and men. Thrombo-occlusive complications of atherosclerosis, including stroke and myocardial infarction, are major causes of morbidity and mortality. Despite intense research efforts, the underlying molecular mechanisms of atherosclerosis are still incompletely understood, how-
* Corresponding author. Tel.: +86 731 5292013. E-mail address: [email protected] (S.-h. Zhou).
ever, many findings have demonstrated the vital role of progenitor cells in the homeostasis of the vessel wall and the mitigation of atherosclerosis. Therefore, based on response-to-injury hypothesis of atherosclerosis, we set up EPC-mediated repair-to-injury hypothesis.
The risk factors of atherosclerosis closely correlated with EPCs numbers and function A growing body of evidence suggests that circulating EPCs play an important role in endothelial cell
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.06.041
A novel hypothesis of atherosclerosis
839
regeneration. Small clinical studies have shown that the number of circulating EPCs inversely correlates with risk factors for atherosclerosis [1,2]. Hill et al. demonstrated a strong correlation between the number of circulating EPCs and the patient’s combined Framingham risk factor score [1]. Cardiovascular risk factors have been closely associated with reduced EPCs numbers and function. All conditions of manifest atherosclerotic disease are accompanied by reduced EPC numbers and migratory capacity [2]. Circulating CD34/KDR-positive progenitor cells are reduced in patients with coronary artery disease (CAD). In addition, EPCs isolated from patients with CAD displayed an impaired migratory response, which was inversely correlated with the number of cardiovascular risk factors [3–5]. Vasculoprotective agents increase the number and function of endothelial progenitor cells improving endothelial function and preventing progression of atherosclerosis. Human studies clearly demonstrate that high EPC levels are associated with reduced cardiovascular event rates underlining the vasculoprotective action of EPCs [6,7]. All major known cardiovascular risk factors negatively influence number of EPCs, migratory capacity, as well as the clonogenic potential of progenitor cells.
erosclerosis, it can lead to reduced flow as a result of narrowing of the lumen and consequent ischemia for downstream tissues. The pathological remodeling usually result in acute coronary syndromes, even acute myocardial infarction these disease frequently go along with elevated numbers of EPCs, which also indicating that EPC-mediated tissue and vessel repair is a ‘‘physiological’’ response of the organism after severe ischemia, simultaneously, the mobilized EPCs are functionally impaired [12–14]. Local injury of the arterial wall also triggers a powerful recruitment of vascular cells, either through in situ proliferation or by engraftment of bone marrow – derived progenitor cells [15,16]. This process of repair can be misguided and contribute to vascular lesion progression [17,18]. As a general rule, the repair is rapid and successful and the inflammatory reaction are self-limited [19], however, Failure to repair the arterial wall in response to inflammatory signals will further promote atherogenesis and hence create a positive feedback loop that propagates vessel injury.
The crucial roles of progenitor cells in repair-to-injury process
In the presence of competent bone marrow, the repair to injury of arterial always can be successful or self-limited.The inflammatory reaction is self-contained because the repair of the arterial wall results in the discontinuation of the stimulus that had triggered the inflammatory reaction. In contrast, in the absence of competent marrow, an arterial lesion has no opportunity to become repaired, and this lack of repair contributes to perpetuating and even intensifying of the atherosclerotic inflammation, with progressive senescence and dysfunctional remodeling of the arterial wall. Most likely, the observed impairment of progenitor cells in these patients is attributable to the accumulation of cardiovascular risk factors resulting in a reduced regenerative potential [2]. Cardiovascular risk factors, especially Aging, can lead to depletion of bone marrow cells capable of repair of the arterial wall [20–22]. Indeed, the depletion of bone marrow–derived progenitor cells may account for a large fraction of the aging risk in the development of vascular disorders [22]. Such depletion of competent cells may involve the loss of production of progenitors by a dysfunctional marrow or the marrow production of dysfunctional progenitor cells that are therefore incapable of
Various studies have underlined the important role of bone marrow–derived endothelial progenitor cells (EPCs) in vasculogenesis and angiogenesis of ischemic tissue. All conditions of manifest atherosclerotic disease are accompanied by reduced EPC numbers and migratory capacity [2]. Most likely, the observed impairment of progenitor cells in these patients is attributable to the accumulation of cardiovascular risk factors resulting in a reduced regenerative potential. According to the response-to-injury hypothesis, cardiovascular risk factors induce a chemical or mechanical injury of the endothelium that triggers and finally results in endothelial dysfunction [8]. The latter is a prerequisite of atherosclerosis [9–11]. The injured arterial wall mounts a profound systemic response that involves a cascade of molecular and cellular events to promote the repair of the vessel wall.The repair and remodeling of the arterial wall are regulated by circulation of progenitor cells by the bone marrow and other organs. Many evidences have shown EPCs plays a crucial roles in this process of repair and remodeling.When remodeling becomes pathological, especially in advanced ath-
Prerequisites of atherosclerosis: Cardiovascular risk factors and depletion of bone marrow
840 repair [22]. Competent progenitors might also be produced but may not be released by the marrow. It is still possible that repair-competent progenitor cells are produced and circulate but are unable to latch onto arterial lesions, once latched, these competent progenitor cells might be unable to mount a successful repair process as a result of local hemodynamic and other factors.
Clinical implications Strengthening the regenerative capacity of the organism seems one way to reduce the incidence of atherosclerosis. This may have important therapeutic implications, but only a few studies have concentrated on the role of EPCs in the prevention and therapy of atherosclerosis. In the future, the use of EPCs for vascular repair may be important for choosing therapy strategies with a maximized benefit for the patient. This implicates that improvement of number and function of EPCs may result in an effective vasculoprotection preventing the initiation and progression of atherosclerosis. There is good evidence that statins and ACE inhibitor mediate at least part of their pleiotrophic, vasculoprotective action via EPCs. In addition, physical activity and estrogens have been shown to influence EPC number and function [23]. Experimental data demonstrate that systemic transfusion of healthy EPCs in conditions of arterial EC denudation can enhance re-endothelialization, resulting in a diminished neointima formation. Furthermore, transfusion of healthy EPCs derived from wild-type mice in apolipoprotein E knockout mice can improve hypercholesterolemia-induced endothelial dysfunction and the development of atherosclerosis [24]. These results suggest that EPCs are equipped with efficient protection systems, making these cells even more attractive for cell therapy.These topics represent exciting future areas of investigation and might have a profound impact on our understanding of vascular disease and repair.
References [1] Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003;348:593–600. [2] Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 2001;89: E1–7.
Zhang et al. [3] Chen JZ, Zhu JH, Wang XX, Zhu JH, Xie XD, Sun J, et al. Effects of homocysteine on number and activity of endothelial progenitor cells from peripheral blood. J Mol Cell Cardiol 2004;36:233–9. [4] Suh W, Kim KL, Choi JH, Lee YS, Lee JY, Kim JM, et al. Creactive protein impairs angiogenic functions and decreases the secretion of arteriogenic chemo-cytokines in human endothelial progenitor cells. Biochem Biophys Res Commun 2004;321:65–71. [5] Verma S, Kuliszewski MA, Li SH, Szmitko PE, Zucco L, Wang CH, 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 2004;109:2058–67. [6] Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 2005;353:999–1007. [7] Schmidt-Lucke C, Rossig L, Fichtlscherer S, Vasa M, Britten M, Kamper U, et al. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation 2005;111:2981–7. [8] Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999;340:115–26. [9] Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 2001;104:2673–8. [10] Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000;101:1899–906. [11] Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes Jr DR, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000;101:948–54. [12] Goldschmidt-Clermont PJ, Kandzari DE, Sketch Jr MH, Phillips HR. Inflammation, platelets, and glycoprotein IIb/ IIIa inhibitors. J Invasive Cardiol 2002;14(suppl E):18E–26E. [13] Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-, in vivo. J Clin Endocrinol Metab 1997;82:4196–200. [14] Goldschmidt-Clermont PJ. Loss of bone marrow – derived vascular progenitor cells leads to inflammation and atherosclerosis. Am Heart J 2003;146(suppl):S5–S12. [15] Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964–7. [16] Lin Y, Weisdorf DJ, Solovey A, Hebbel RP. Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest 2000;105:71–7. [17] Shi W, Haberland ME, Jien ML, Shih DM, Lusis AJ. Endothelial responses to oxidized lipoproteins determine genetic susceptibility to atherosclerosis in mice. Circulation 2000;102:75–81. [18] Epstein SE. The multiple mechanisms by which infection may contribute to atherosclerosis development and course. Circ Res 2002;90:2–4. [19] Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, Wang T, Gregg D, Ramaswami P, et al. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation 2003;108:457–63. [20] Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, Wang T, Gregg D, Ramaswami P, et al. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation 2003;108: 457–63.
A novel hypothesis of atherosclerosis [21] Sata M, Saiura A, Kunisato A, Tojo A, Okada S, Tokuhisa T, et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 2002;8:403–9. [22] Goldschmidt-Clermont PJ, Peterson ED. On the memory of a chronic illness. Sci Aging Knowl Environ 2003;2003:re8.
841 [23] Nikos Werner. Georg Nickenig influence of cardiovascular risk factors on endothelial progenitor cells. Arterioscl Throm Vas Biol 2006;26:257. [24] Goldschmidt-Clermont PJ. Loss of bone marrow – derived vascular progenitor cells leads to inflammation and atherosclerosis. Am Heart J 2003;146(suppl):S5–S12.