Background Erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF) are both potential novel therapeutics for use after myocardial infarction (MI).However,their underlying mechanisms remain unclear and the efficacy of monotherapy with EPO or G-CSF is also controversial.Therefore,we investigated the effects of combined treatment with EPO and G-CSF on neovascularization and cardiac function in post-infarction rats and explored the potential mechanisms.Methods Four groups of rats were used:control (saline injection after MI,i.h.),EPO (a single dose of 5 000 IU/kg after MI,i.h.),G-CSF (a dose of 50 μg· kg-1· d-1 for 5 days after MI,i.h.),and both EPO and G-CSF (EPO+G-CSF,using the same regiment as above).Cardiac function was assessed by echocardiography before and 1 day,7 days,14 days and 21 days after MI.CD34+/Flk-1+ cells in the peripheral blood were evaluated by flow cytometry before and 3 days,5 days and 7 days after MI.The infarct area and angiogenesis in the peri-infarct area were analyzed.The mRNA and protein expression of vascular endothelial growth factor (VEGF) and stromal-derived factor-1α (SDF-1α) in the peri-infarct area were detected by real-time quantitative RT-PCR and West blotting.Results Compared with the control and monotherapy groups,the EPO+G-CSF group had significantly increased CD34+/ Flk-1+ endothelial progenitor calls (EPCs)in the peripheral blood (P ＜0.05),up-regulated VEGF and SDF-1α levels in the peri-infarct region (P ＜0.05),enhanced capillary density (P ＜0.05),reduced infarct size (P ＜0.05) and improved cardiac structure and function (P ＜0.05).G-CSF alone did not dramatically increase EPCs in the peripheral blood,enhance capillary density in the peri-infarct area or reduce infarct size compared with the control group.Conclusions Combined treatment with EPO and G-CSF increased EPCs mobilization,up-regulated VEGF and SDF-1α levels in the post-infarction microenvironment,subsequently enhanced neovascularization in the peri-infarct region and reduced infarct size.All factors contributed to its beneficial effects on cardiac function in post-infarction rats.