Erythropoietin Stimulates Normal Endothelial Progenitor Cell-Mediated Endothelial Turnover, but Attributes to Neovascularization Only in the Presence of Local Ischemia
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
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.
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.
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.
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. CrossRef
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- Dimmeler S, Zeiher AM. Vascular repair by circulating endothelial progenitor cells: the missing link in atherosclerosis? J Mol Med. 2004;82:671–7. CrossRef
- Ross R. The pathogenesis of atherosclerosis—an update. N Engl J Med. 1986;314:488–500. CrossRef
- Kisseberth WC, Brettingen NT, Lohse JK, Sandgren EP. Ubiquitous expression of marker transgenes in mice and rats. Dev Biol. 1999;214:128–38. CrossRef
- 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. CrossRef
- 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.
- 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.
- Dimmeler S, Zeiher AM, Schneider MD. Unchain my heart: the scientific foundations of cardiac repair. J Clin Invest. 2005;115:572–83.
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- Brines M, Cerami A. Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci. 2005;6:484–94. CrossRef
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- Steinbrook R. Erythropoietin, the FDA, and oncology. N Engl J Med. 2007;356:2448–51. CrossRef
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- 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. CrossRef
- Erythropoietin Stimulates Normal Endothelial Progenitor Cell-Mediated Endothelial Turnover, but Attributes to Neovascularization Only in the Presence of Local Ischemia
Cardiovascular Drugs and Therapy
Volume 22, Issue 4 , pp 265-274
- Cover Date
- Print ISSN
- Online ISSN
- Springer US
- Additional Links
- endothelial function
- heart failure
- endothelial progenitor cells
- Industry Sectors
- Author Affiliations
- 1. Department of Cardiology, Thoraxcenter, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB, Groningen, The Netherlands