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Published in:

01-08-2008

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

Authors: 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

Published in: Cardiovascular Drugs and Therapy | Issue 4/2008

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.

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

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

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 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

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

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 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

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

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.

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.

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.

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.

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.

Ross R. The pathogenesis of atherosclerosis—an update. N Engl J Med. 1986;314:488–500.PubMedCrossRef

15.

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.

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.

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.

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.

Dimmeler S, Zeiher AM, Schneider MD. Unchain my heart: the scientific foundations of cardiac repair. J Clin Invest. 2005;115:572–83.PubMed

20.

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.

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.

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.

Brines M, Cerami A. Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci. 2005;6:484–94.PubMedCrossRef

24.

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.

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.

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.

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.

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.

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.

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.

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.

Steinbrook R. Erythropoietin, the FDA, and oncology. N Engl J Med. 2007;356:2448–51.PubMedCrossRef

33.

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.

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.

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.

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

Title: Erythropoietin Stimulates Normal Endothelial Progenitor Cell-Mediated Endothelial Turnover, but Attributes to Neovascularization Only in the Presence of Local Ischemia
Authors: 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
Publication date: 01-08-2008
Publisher: Springer US
Published in: Cardiovascular Drugs and Therapy / Issue 4/2008
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI: https://doi.org/10.1007/s10557-008-6094-y

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

Abstract

Purpose

Methods

Results

Conclusions

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