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01.08.2008

Erythropoietin Stimulates Normal Endothelial Progenitor Cell-Mediated Endothelial Turnover, but Attributes to Neovascularization Only in the Presence of Local Ischemia

verfasst von: B. Daan Westenbrink, Hisko Oeseburg, Lennaert Kleijn, Pim van der Harst, Anne M. S. Belonje, Adriaan A. Voors, Regien G. Schoemaker, Rudolf A. de Boer, Dirk J. van Veldhuisen, Wiek H. van Gilst

Erschienen in: Cardiovascular Drugs and Therapy | Ausgabe 4/2008

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Abstract

Purpose

We aimed to evaluate whether ischemia is required for erythropoietin (EPO) induced stimulation of endothelial progenitor cells (EPCs) and their related effects on endothelial and cardiac function.

Methods

Bone marrow of rats was replaced by transgenic cells to allow tracking of EPCs. Ischemic heart failure was induced by left coronary artery ligation to induce myocardial infarction (MI) and control rats received a sham procedure. Three weeks after surgery, rats were randomized to receive EPO (darbepoetin alfa 40 μg/kg per 3 weeks) or vehicle and were sacrificed 9 weeks after surgery.

Results

In all treated groups, EPO significantly increased circulating EPCs and their incorporation into the endothelium of the ischemic and non-ischemic hearts as well as in the control organs; kidney and liver. This was associated with significantly improved endothelial function, which was strongly correlated with circulating EPCs (R = 0.7, p < 0.01). However, additional EPCs preferentially homed to the ischemic MI borderzone (p < 0.01) resulting in specific EPO-induced improvement of cardiac microvascularization and performance only in ischemic hearts (all p < 0.05). The differential stimulation of neovascularization by EPO was associated with increased EPO-receptor and VEGF expression in ischemic hearts only.

Conclusions

In general, EPO stimulates normal endothelial progenitor cell-mediated endothelial turnover, but improves cardiac microvascularization and function only in the presence of ischemia.
Literatur
1.
Zurück zum Zitat Hamed S, Barshack I, Luboshits G, Wexler D, Deutsch V, Keren G, George J. Erythropoietin improves myocardial performance in doxorubicin-induced cardiomyopathy. Eur Heart J. 2006;27:1876–83.PubMedCrossRef Hamed S, Barshack I, Luboshits G, Wexler D, Deutsch V, Keren G, George J. Erythropoietin improves myocardial performance in doxorubicin-induced cardiomyopathy. Eur Heart J. 2006;27:1876–83.PubMedCrossRef
2.
Zurück zum Zitat Hirata A, Minamino T, Asanuma H, Fujita M, Wakeno M, Myoishi M, et al. Erythropoietin enhances neovascularization of ischemic myocardium and improves left ventricular dysfunction after myocardial infarction in dogs. J Am Coll Cardiol. 2006;48:176–84.PubMedCrossRef Hirata A, Minamino T, Asanuma H, Fujita M, Wakeno M, Myoishi M, et al. Erythropoietin enhances neovascularization of ischemic myocardium and improves left ventricular dysfunction after myocardial infarction in dogs. J Am Coll Cardiol. 2006;48:176–84.PubMedCrossRef
3.
Zurück zum Zitat Li L, Takemura G, Li Y, Miyata S, Esaki M, Okada H, et al. Preventive effect of erythropoietin on cardiac dysfunction in doxorubicin-induced cardiomyopathy. Circulation. 2006;113:535–43.PubMedCrossRef Li L, Takemura G, Li Y, Miyata S, Esaki M, Okada H, et al. Preventive effect of erythropoietin on cardiac dysfunction in doxorubicin-induced cardiomyopathy. Circulation. 2006;113:535–43.PubMedCrossRef
4.
Zurück zum Zitat Li Y, Takemura G, Okada H, Miyata S, Maruyama R, Li L, Higuchi M, et al. Reduction of inflammatory cytokine expression and oxidative damage by erythropoietin in chronic heart failure. Cardiovasc Res. 2006;71:684–94.PubMedCrossRef Li Y, Takemura G, Okada H, Miyata S, Maruyama R, Li L, Higuchi M, et al. Reduction of inflammatory cytokine expression and oxidative damage by erythropoietin in chronic heart failure. Cardiovasc Res. 2006;71:684–94.PubMedCrossRef
5.
Zurück zum Zitat Prunier F, Pfister O, Hadri L, Liang L, Del MF, Liao R, et al. Delayed erythropoietin therapy reduces post-MI cardiac remodeling only at a dose that mobilizes endothelial progenitor cells. Am J Physiol Heart Circ Physiol. 2007;292:H522–529.PubMedCrossRef Prunier F, Pfister O, Hadri L, Liang L, Del MF, Liao R, et al. Delayed erythropoietin therapy reduces post-MI cardiac remodeling only at a dose that mobilizes endothelial progenitor cells. Am J Physiol Heart Circ Physiol. 2007;292:H522–529.PubMedCrossRef
6.
Zurück zum Zitat van der Meer P, Lipsic E, Henning RH, Boddeus K, van der Velden J, Voors AA, van Veldhuisen DJ, van Gilst WH, Schoemaker RG. Erythropoietin induces neovascularization and improves cardiac function in rats with heart failure after myocardial infarction. J Am Coll Cardiol. 2005;46:125–33.PubMedCrossRef van der Meer P, Lipsic E, Henning RH, Boddeus K, van der Velden J, Voors AA, van Veldhuisen DJ, van Gilst WH, Schoemaker RG. Erythropoietin induces neovascularization and improves cardiac function in rats with heart failure after myocardial infarction. J Am Coll Cardiol. 2005;46:125–33.PubMedCrossRef
7.
Zurück zum Zitat van Veldhuisen DJ, Dickstein K, Cohen-Solal A, Lok DJ, Wasserman SM, Baker N, et al. Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia. Eur Heart J 2007;28:2208–16.PubMedCrossRef van Veldhuisen DJ, Dickstein K, Cohen-Solal A, Lok DJ, Wasserman SM, Baker N, et al. Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia. Eur Heart J 2007;28:2208–16.PubMedCrossRef
8.
Zurück zum Zitat Westenbrink BD, Lipsic E, van der Meer P, van der Harst P, Oeseburg H, Du Marchie Sarvaas GJ, et al. Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization. Eur Heart J. 2007;28:2018–27.PubMedCrossRef Westenbrink BD, Lipsic E, van der Meer P, van der Harst P, Oeseburg H, Du Marchie Sarvaas GJ, et al. Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization. Eur Heart J. 2007;28:2018–27.PubMedCrossRef
9.
Zurück zum Zitat Bahlmann FH, Song R, Boehm SM, Mengel M, von WR, Lindschau C, et al. Low-dose therapy with the long-acting erythropoietin analogue darbepoetin alpha persistently activates endothelial Akt and attenuates progressive organ failure. Circulation. 2004;110:1006–12.PubMedCrossRef Bahlmann FH, Song R, Boehm SM, Mengel M, von WR, Lindschau C, et al. Low-dose therapy with the long-acting erythropoietin analogue darbepoetin alpha persistently activates endothelial Akt and attenuates progressive organ failure. Circulation. 2004;110:1006–12.PubMedCrossRef
10.
Zurück zum Zitat Heeschen C, Aicher A, Lehmann R, Fichtlscherer S, Vasa M, Urbich C, et al. Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood. 2003;102:1340–6.PubMedCrossRef Heeschen C, Aicher A, Lehmann R, Fichtlscherer S, Vasa M, Urbich C, et al. Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood. 2003;102:1340–6.PubMedCrossRef
11.
Zurück zum Zitat Imamura R, Moriyama T, Isaka Y, Namba Y, Ichimaru N, Takahara S, et al. Erythropoietin protects the kidneys against ischemia reperfusion injury by activating hypoxia inducible factor-1alpha. Transplantation. 2007;83:1371–9.PubMedCrossRef Imamura R, Moriyama T, Isaka Y, Namba Y, Ichimaru N, Takahara S, et al. Erythropoietin protects the kidneys against ischemia reperfusion injury by activating hypoxia inducible factor-1alpha. Transplantation. 2007;83:1371–9.PubMedCrossRef
12.
Zurück zum Zitat Urao N, Okigaki M, Yamada H, Aadachi Y, Matsuno K, Matsui A, et al. Erythropoietin-mobilized endothelial progenitors enhance reendothelialization via Akt-endothelial nitric oxide synthase activation and prevent neointimal hyperplasia. Circ Res. 2006;98:1405–13.PubMedCrossRef Urao N, Okigaki M, Yamada H, Aadachi Y, Matsuno K, Matsui A, et al. Erythropoietin-mobilized endothelial progenitors enhance reendothelialization via Akt-endothelial nitric oxide synthase activation and prevent neointimal hyperplasia. Circ Res. 2006;98:1405–13.PubMedCrossRef
13.
Zurück zum Zitat Dimmeler S, Zeiher AM. Vascular repair by circulating endothelial progenitor cells: the missing link in atherosclerosis? J Mol Med. 2004;82:671–7.PubMedCrossRef Dimmeler S, Zeiher AM. Vascular repair by circulating endothelial progenitor cells: the missing link in atherosclerosis? J Mol Med. 2004;82:671–7.PubMedCrossRef
14.
15.
Zurück zum Zitat Kisseberth WC, Brettingen NT, Lohse JK, Sandgren EP. Ubiquitous expression of marker transgenes in mice and rats. Dev Biol. 1999;214:128–38.PubMedCrossRef Kisseberth WC, Brettingen NT, Lohse JK, Sandgren EP. Ubiquitous expression of marker transgenes in mice and rats. Dev Biol. 1999;214:128–38.PubMedCrossRef
16.
Zurück zum Zitat van der Harst P, Smilde TD, Buikema H, Voors AA, Navis G, van Veldhuisen DJ, van Gilst WH. Vascular function and mild renal impairment in stable coronary artery disease. Arterioscler Thromb Vasc Biol. 2006;26:379–84.PubMedCrossRef van der Harst P, Smilde TD, Buikema H, Voors AA, Navis G, van Veldhuisen DJ, van Gilst WH. Vascular function and mild renal impairment in stable coronary artery disease. Arterioscler Thromb Vasc Biol. 2006;26:379–84.PubMedCrossRef
17.
Zurück zum Zitat Perticone F, Ceravolo R, Pujia A, Ventura G, Iacopino S, Scozzafava A, et al. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation. 2001;104:191–6.PubMed Perticone F, Ceravolo R, Pujia A, Ventura G, Iacopino S, Scozzafava A, et al. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation. 2001;104:191–6.PubMed
18.
Zurück zum Zitat Treasure CB, Vita JA, Cox DA, Fish RD, Gordon JB, Mudge GH, et al. Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. Circulation. 1990;81:772–9.PubMed Treasure CB, Vita JA, Cox DA, Fish RD, Gordon JB, Mudge GH, et al. Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. Circulation. 1990;81:772–9.PubMed
19.
Zurück zum Zitat Dimmeler S, Zeiher AM, Schneider MD. Unchain my heart: the scientific foundations of cardiac repair. J Clin Invest. 2005;115:572–83.PubMed Dimmeler S, Zeiher AM, Schneider MD. Unchain my heart: the scientific foundations of cardiac repair. J Clin Invest. 2005;115:572–83.PubMed
20.
Zurück zum Zitat Santhanam AV, Smith LA, He T, Nath KA, Katusic ZS. Endothelial progenitor cells stimulate cerebrovascular production of prostacyclin by paracrine activation of cyclooxygenase-2. Circ Res. 2007;100:1379–88.PubMedCrossRef Santhanam AV, Smith LA, He T, Nath KA, Katusic ZS. Endothelial progenitor cells stimulate cerebrovascular production of prostacyclin by paracrine activation of cyclooxygenase-2. Circ Res. 2007;100:1379–88.PubMedCrossRef
21.
Zurück zum Zitat Lindenblatt N, Menger MD, Klar E, Vollmar B. Darbepoetin-alpha does not promote microvascular thrombus formation in mice: role of eNOS-dependent protection through platelet and endothelial cell deactivation. Arterioscler Thromb Vasc Biol. 2007;27:1191–8.PubMedCrossRef Lindenblatt N, Menger MD, Klar E, Vollmar B. Darbepoetin-alpha does not promote microvascular thrombus formation in mice: role of eNOS-dependent protection through platelet and endothelial cell deactivation. Arterioscler Thromb Vasc Biol. 2007;27:1191–8.PubMedCrossRef
22.
Zurück zum Zitat d’Uscio LV, Smith LA, Santhanam AV, Richardson D, Nath KA, Katusic ZS. Essential role of endothelial nitric oxide synthase in vascular effects of erythropoietin. Hypertension. 2007;49:1142–8.PubMedCrossRef d’Uscio LV, Smith LA, Santhanam AV, Richardson D, Nath KA, Katusic ZS. Essential role of endothelial nitric oxide synthase in vascular effects of erythropoietin. Hypertension. 2007;49:1142–8.PubMedCrossRef
23.
Zurück zum Zitat Brines M, Cerami A. Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci. 2005;6:484–94.PubMedCrossRef Brines M, Cerami A. Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci. 2005;6:484–94.PubMedCrossRef
24.
Zurück zum Zitat Kalkman EA, Bilgin YM, van der Harst P, van Suylen RJ, Saxena PR, Schoemaker RG. Determinants of coronary reserve in rats subjected to coronary artery ligation or aortic banding. Cardiovasc Res. 1996;32:1088–95.PubMedCrossRef Kalkman EA, Bilgin YM, van der Harst P, van Suylen RJ, Saxena PR, Schoemaker RG. Determinants of coronary reserve in rats subjected to coronary artery ligation or aortic banding. Cardiovasc Res. 1996;32:1088–95.PubMedCrossRef
25.
Zurück zum Zitat Sano M, Minamino T, Toko H, Miyauchi H, Orimo M, Qin Y, et al. p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature. 2007;446:444–8.PubMedCrossRef Sano M, Minamino T, Toko H, Miyauchi H, Orimo M, Qin Y, et al. p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature. 2007;446:444–8.PubMedCrossRef
26.
Zurück zum Zitat Wang L, Zhang Z, Wang Y, Zhang R, Chopp M. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke. 2004;35:1732–7.PubMedCrossRef Wang L, Zhang Z, Wang Y, Zhang R, Chopp M. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke. 2004;35:1732–7.PubMedCrossRef
27.
Zurück zum Zitat Nakano M, Satoh K, Fukumoto Y, Ito Y, Kagaya Y, Ishii N, et al. Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice. Circ Res. 2007;100:662–9.PubMedCrossRef Nakano M, Satoh K, Fukumoto Y, Ito Y, Kagaya Y, Ishii N, et al. Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice. Circ Res. 2007;100:662–9.PubMedCrossRef
28.
Zurück zum Zitat Zentilin L, Tafuro S, Zacchigna S, Arsic N, Pattarini L, Sinigaglia M, et al. Bone marrow mononuclear cells are recruited to the sites of VEGF-induced neovascularization but are not incorporated into the newly formed vessels. Blood. 2006;107:3546–54.PubMedCrossRef Zentilin L, Tafuro S, Zacchigna S, Arsic N, Pattarini L, Sinigaglia M, et al. Bone marrow mononuclear cells are recruited to the sites of VEGF-induced neovascularization but are not incorporated into the newly formed vessels. Blood. 2006;107:3546–54.PubMedCrossRef
29.
Zurück zum Zitat Nitta K, Uchida K, Kimata N, Honda K, Kobayashi H, Kawashima A, et al. Recombinant human erythropoietin stimulates vascular endothelial growth factor release by glomerular endothelial cells. Eur J Pharmacol. 1999;373:121–4.PubMedCrossRef Nitta K, Uchida K, Kimata N, Honda K, Kobayashi H, Kawashima A, et al. Recombinant human erythropoietin stimulates vascular endothelial growth factor release by glomerular endothelial cells. Eur J Pharmacol. 1999;373:121–4.PubMedCrossRef
30.
Zurück zum Zitat Beleslin-Cokic BB, Cokic VP, Yu X, Weksler BB, Schechter AN, Noguchi CT. Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood. 2004;104:2073–80.PubMedCrossRef Beleslin-Cokic BB, Cokic VP, Yu X, Weksler BB, Schechter AN, Noguchi CT. Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood. 2004;104:2073–80.PubMedCrossRef
31.
Zurück zum Zitat Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071–84.PubMedCrossRef Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071–84.PubMedCrossRef
32.
33.
Zurück zum Zitat Lipsic E, Westenbrink BD, van der Meer P, van der Harst P, Voors AA, van Veldhuisen DJ, et al. Low-dose erythropoietin improves cardiac function in experimental heart failure without increasing haematocrit. Eur J Heart Fail. 2008;10:22–9.PubMedCrossRef Lipsic E, Westenbrink BD, van der Meer P, van der Harst P, Voors AA, van Veldhuisen DJ, et al. Low-dose erythropoietin improves cardiac function in experimental heart failure without increasing haematocrit. Eur J Heart Fail. 2008;10:22–9.PubMedCrossRef
34.
Zurück zum Zitat Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M, et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science. 2004;305:239–42.PubMedCrossRef Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M, et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science. 2004;305:239–42.PubMedCrossRef
35.
Zurück zum Zitat Kissel CK, Lehmann R, Assmus B, Aicher A, Honold J, Fischer-Rasokat U, et al. Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with postinfarction heart failure. J Am Coll Cardiol. 2007;49:2341–9.PubMedCrossRef Kissel CK, Lehmann R, Assmus B, Aicher A, Honold J, Fischer-Rasokat U, et al. Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with postinfarction heart failure. J Am Coll Cardiol. 2007;49:2341–9.PubMedCrossRef
36.
Zurück zum Zitat van der Harst P, van der Steege G, de Boer RA, Voors AA, Hall AS, Mulder MJ, et al. Telomere length of circulating leukocytes is decreased in patients with chronic heart failure. J Am Coll Cardiol. 2007;49:1459–64.PubMedCrossRef van der Harst P, van der Steege G, de Boer RA, Voors AA, Hall AS, Mulder MJ, et al. Telomere length of circulating leukocytes is decreased in patients with chronic heart failure. J Am Coll Cardiol. 2007;49:1459–64.PubMedCrossRef
Metadaten
Titel
Erythropoietin Stimulates Normal Endothelial Progenitor Cell-Mediated Endothelial Turnover, but Attributes to Neovascularization Only in the Presence of Local Ischemia
verfasst von
B. Daan Westenbrink
Hisko Oeseburg
Lennaert Kleijn
Pim van der Harst
Anne M. S. Belonje
Adriaan A. Voors
Regien G. Schoemaker
Rudolf A. de Boer
Dirk J. van Veldhuisen
Wiek H. van Gilst
Publikationsdatum
01.08.2008
Verlag
Springer US
Erschienen in
Cardiovascular Drugs and Therapy / Ausgabe 4/2008
Print ISSN: 0920-3206
Elektronische ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-008-6094-y

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