Ischemia induces angiogenesis as a compensatory response. Although ischemia is known to causes synthesis and release of calcitonin gene-related peptide (CGRP), it is not clear whether CGRP regulates angiogenesis under ischemia and how does it function. Thus we investigated the role of CGRP in angiogenesis and the involved mechanisms. We found that CGRP level was increased in the rat hindlimb ischemic tissue. The expression of exogenous CGRP by adenovirus vectors enhanced blood flow recovery and increased capillary density in ischemic hindlimbs. In vitro, CGRP promoted human umbilical vein endothelial cell (HUVEC) tube formation and migration. Further more, CGRP activated AMP-activated protein kinase (AMPK) both in vivo and in vitro, and pharmacological inhibition of CGRP and cAMP attenuated the CGRP-activated AMPK in vitro. CGRP also induced endothelial nitric oxide synthase (eNOS) phosphorylation in HUVECs at Ser1177 and Ser633 in a time-dependent manner, and such effects were abolished by AMPK inhibitor Compound C. As well, Compound C blocked CGRP-enhanced HUVEC tube formation and migration. These findings indicate that CGRP promotes angiogenesis by activating the AMPK-eNOS pathway in endothelial cells.