Recent studies have shown that side population (SP) cells, isolated from adult myocardium, represent a distinct cardiac progenitor cell population that exhibits functional cardiomyogenic differentiation. However, information on the intrinsic characteristics and endothelial potential, of cardiac SP cells, is limited. In this study, we demonstrate that cardiac SP cells have endothelial differentiation potential in vitro and increase the restoration of blood flow when injected into an ischemic murine hindlimb. In RT-PCR or real-time PCR, expression of early cardiac transcription factors such as GATA4, atrial natriuretic factor and Nkx2.5 was higher in freshly isolated adult heart-SP cells compared to the bone marrow-SP cells. Expression of CD31, vascular endothelial growth factor (VEGF) receptor-1 (VEGFR1) and VEGFR-2, Tie1, and Tie2 mRNA were ~24.9, ~430, ~860, ~9.9 and ~188-fold higher in adult heart-SP cells than in the bone marrow-SP cells, respectively. After treatment with VEGF, for 28 days, cardiac SP cells differentiated into endothelial cells expressing von Willebrand factor as determined by immunocytochemistry. Furthermore, CD31 and VEGF mRNA was expressed ~3.0- and ~4.2-fold in VEGF-treated adult heart SP cells than control group when assessed by real-time RT-PCR. To investigate the endothelial potential, of adult heart-SP cells in vivo, we performed transplantation of adult heart-SP cells to the ischemic hindlimb. A laser Doppler perfusion image analyses revealed a significantly (p < 0.05) augmented ratio of ischemic/normal hindlimb blood flow in the adult heart-SP cell-transplanted group (n=30) compared with the saline-treated controls (n=30) at postoperative days: 7, 14, 21 and 28. Most mice injected with saline typically had extensive limb necrosis, leading to autoamputation of the ischemic limb. By contrast, among mice receiving adult heart -SP cells, limb salvage occurred in 10 of 30 animals and tip necrosis occurred 9 of 30 animals. In conclusion, cardiac SP cells may function as a cardiac progenitor cell population sharing the potential to transdifferentiate into angiogenic lineages, and they may contribute to regeneration of injured heart tissues.