We hypothesized that the overexpression of early growth response factor-1 (Egr-1), which plays a pivotal role in the activation of many genes under stress conditions, might induce multiple genes involved in vessel formation and thereby contribute to the revascularization of ischemic muscle. To test this hypothesis, adenoviral vectors carrying the genes for Egr-1 and Egr-1* (a constitutively active form of Egr-1) were made and transduced into primary human skeletal myocytes. RNA and protein analyses revealed that angiogenesis-related genes such as bFGF, PDGF-A, PDGF-B, IGF-II, and TGF-棺1 were significantly upregulated. Co-culture assay of the paracrine effects of transduced myocytes indicated that the Ad-Egr-1* group significantly promoted proliferation of endothelial cells and regrowth from the wound edge following scratch injury. To further evaluate the angiogenic potential of Egr-1* in muscle tissue, Ad-Egr-1* was injected into the tibialis anterior muscle of mice (Balb/c), followed by explant cultures in growth-factor-reduced Matrigel. Many sprouted capillary-like structures were observed in the Ad-Egr-1*-transduced muscle compared with minimal sprouting from the Ad-LacZ-injected muscle (The mean area of the vessel-like structures: 7.2 mm짼 vs. less than 0.3 mm짼, n = 8, p < 0.05), suggesting an angiogenic activity of Egr-1*. Next we evaluated Ad-Egr-1* in vivo in a murine model of hindlimb ischemia (Balb/c), in which the superficial femoral artery was ligated twice. Compared with the slow revascularization in the PBS- or Ad-LacZ injected group, a rapid increase in tissue perfusion was observed in the Ad-Egr-1*-injected group and the difference in the measured flux ratio was statistically significant at day 7 (0.28 짹 0.04 vs. 0.13 짹 0.02, n = 4-7, p < 0.05). These results suggest that Egr-1* plays an important role in vascular recovery after occlusion and thus represent a potential target for therapeutic revascularization.