European Heart Journal Advance Access originally published online on June 17, 2007
European Heart Journal 2007 28(16):2018-2027; doi:10.1093/eurheartj/ehm177
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Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization
ic1,2
1 Department of Cardiology, Thoraxcenter, University Medical Center Groningen, University of Groningen, Hanzeplein 1, PO Box 30001, 9700 RB Groningen, The Netherlands
2 Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, The Netherlands
3 Department of Pediatric Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands
Received 18 February 2007; revised 3 April 2007; accepted 13 April 2007; online publish-ahead-of-print 17 June 2007.
* Corresponding author. Tel: +31 50 361 3876; fax: +31 50 361 4391. E-mail address: b.d.westenbrink{at}thorax.umcg.nl
Aims: Erythropoietin (EPO) improves cardiac function and induces neovascularization in chronic heart failure (CHF), although the exact mechanism has not been elucidated. We studied the effects of EPO on homing and incorporation of endothelial progenitor cells (EPC) into the myocardial microvasculature and myocardial expression of angiogenic factors.
Methods and results: CHF was induced in rats by coronary artery ligation resulting in myocardial infarction (MI) after bone marrow had been replaced by human placental alkaline phosphatase (hPAP) transgenic cells. We studied the effects of darbepoetin alfa treatment (EPO, 40 µg/kg, every 3 weeks, starting 3 weeks after MI) on longitudinal changes in left ventricular (LV) function, circulating EPC, myocardial histology, and expression of vascular endothelial growth factor (VEGF) determined 9 weeks after MI. EPO prevented LV-dilatation and improved cardiac function (all P < 0.05), which was associated with 42% increased capillary growth (P < 0.01). EPO-induced mobilization of EPC from the bone marrow (P < 0.01), which resulted in a three-fold increased homing of EPC into the cardiac microvasculature. The percentage of the endothelium that consisted of bone marrow derived cells was significantly increased (3.9 ± 0.5 vs. 11.4 ± 1%, P < 0.001) comprising 30% of the newly formed capillaries. In addition, EPO treatment resulted in a 4.5-fold increased myocardial expression of VEGF, which correlated strongly with neovascularization (r = 0.67; P < 0.001). VEGF was equally expressed by endothelial cells of myocardial and bone marrow origin.
Conclusion: EPO-induced neovascularization in post-MI heart failure is mediated through a combination of EPC recruitment from the bone marrow and increased myocardial expression of VEGF.
Key Words: Erythropoietin • Endothelial progenitor cell • Neovascularization • Chronic heart failure
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