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resulting in myocardial infarction (MI) after bone marrow had been replaced by 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 microg/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.