Aims: We have previously demonstrated that low-energy extracorporeal cardiac shock wave (SW) therapy improves myocardial ischemia through enhanced myocardial angiogenesis in a porcine model of chronic myocardial ischemia and in patients with refractory angina pectoris. However, the detailed molecular mechanisms for the SW-induced angiogenesis remain unclear. In this study, we thus examined the effects of SW irradiation on intracellular signaling pathways in vitro. Methods and Results: Cultured human umbilical vein endothelial cells (HUVECs) were treated with 800 shots of low-energy SW (1 Hz at an energy level of 0.03 mJ/mm2). The SW therapy significantly up-regulated mRNA expression and protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). The SW therapy also enhanced phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2) and Akt. Furthermore, the SW therapy enhanced phosphorylation of caveolin-1 and the expression of HUTS-4 that represents β₁-integrin activity. These results suggest that caveolin-1 and β₁-integrin are involved in the SW-induced activation of angiogenic signaling pathways. To further examine the signaling pathways involved in the SW-induced angiogenesis, HUVECs were transfected with siRNA of either β₁-integrin or caveolin-1. Knockdown of either caveolin-1 or β₁-integrin suppressed the SW-induced phosphorylation of Erk1/2 and Akt and up-regulation of VEGF and eNOS. Knockdown of either caveolin-1 or β₁-integrin also suppressed SW-induced enhancement of HUVEC migration in scratch assay. Conclusions: These results suggest that activation of mechanosensors on cell membranes, such as caveolin-1 and β₁-integrin, and subsequent phosphorylation of Erk and Akt may play pivotal roles in the SW-induced angiogenesis.