Previous studies have demonstrated extracorporeal cardiac shock waves (ECSW) could induce angiogenesis and improves myocardial function in patients with coronary heart diseases as a safe, effective, and non-invasive angiogenic approach. The endothelial progenitor cells (EPCs) can migrate to the ischemic myocardium and differentiate into vascular endothelial cells, thus promoting the angiogenesis. Whether ECSW can improve the angiogenic ability of EPCs is unclear. This topic studied the effects of ECSW Therapy on EPCs functions and related signal transduction pathways. The bone marrow-derived EPCs of SD rats were isolated by the density centrifugation method. After treatment with ECSW (500 shots at 0.09 mJ/mm2), the cell viability, anti-apoptosis, migration, and tube formation of EPCs were significantly improved. In addition, the expressions of phosphorylated AKT and ERK were increased after ECSW treatment, the expressions of downstream signaling molecules eNOS and Bcl-2 were also increased, but the expressions of Bax and Caspase3 were decreased. However, these beneficial effects can be inhibited by PI3K/AKT inhibitor LY294002 and MEK/ERK inhibitor PD98059. Together, ECSW can promote the cell viability, migration, and angiogenic ability of EPCs and inhibit the apoptosis of EPCs through the PI3K/AKT and MEK/ERK signaling pathways. The mechanism may be related to promoting the expressions of downstream p-eNOS and anti-apoptotic protein Bcl-2 and inhibiting the expressions of pro-apoptotic protein Bax and Caspase3 through the PI3K/AKT and MEK/ERK signaling pathways. AJTR Copyright © 2020.