Angiogenesis is an important repair mechanism in response to ischemia/reperfusion (I/R) injury through increasing blood flow and oxygen supply. Previous studies suggested that growth differentiation factor 15 (GDF-15) was one of the most important factors responsible for promoting the angiogenesis process during cardiac ischemia. Here we tested the hypothesis that GDF-15 could promote angiogenesis via HIF-1α/VEGF dependent signaling pathway. Impaired angiogenic response was significantly improved, VEGF expression up-regulated and p53 inhibited by GDF-15 in hypoxic human umbilical vein endothelial cells (HUVECs). Expression of hypoxia-inducible factor 1-alpha (HIF-1α), an important transcriptional factor linked with angiogenesis, was significantly down-regulated post 24 h hypoxia, HIF-1α expression could be significantly up-regulated and HIF-1α nuclear translocation significantly enhanced by pretreatment with GDF-15 in hypoxic HUVECs. Knock-down HIF-1α by small interference RNA (siRNA) abolished GDF-15-mediated angiogenic effect and suppressed VEGF expression. Further experiments showed that GDF-15 activated HIF-1α signal via stabilizing p53-MDM2 complex and MDM2-mediated p53 ubiquitylation. Nutlin-3, an Hdm2 antagonist, promoted p53 nuclear translocation and attenuated GDF-15-induced activation of HIF-1α and downstream VEGF signaling in hypoxic HUVECs. Taken together, our results suggested that GDF-15 promoted angiogenesis in hypoxic HUVECs possibly through inhibiting p53 signal, which subsequently enhanced and stabolized HIF-1α expression, and up-regulated the related downstream angiogenic signaling.