Zinc finger protein 667 (ZNF667, also referred as Mipu1), a widely expressed KRAB/c 2 H 2 -type zinc finger transcription factor, can protect against hypoxic-ischemic myocardial injury. Pro-angiogenesis is regarded as a promising strategy for the treatment of acute myocardial infarction (AMI). However, whether ZNF667 is involved in the angiogenesis following AMI remains to be elucidated. The present study reported that the expression of ZNF667 in cd31-positive endothelial cells (Ecs) was upregulated in the heart of AMI mice. Hypoxic challenge (1% oxygen) promoted the mRNA and protein expression of ZNF667 in the human umbilical vein endothelial cells (HUVEcs) in a time-dependent manner. Moreover, ZNF667 promoted hypoxia-induced invasion and tube formation of HUVEcs. Mechanically, ZNF667 could directly bind to the promoter of anti-angiogenic gene VASH1 and inhibit its expression. consequently, VASH1 overexpression abolished hypoxic challenge or ZNF667 overexpression-induced invasion and tube formation of HUVEcs. Further bioinformatic analyses suggested that overexpression of ZNF667 or knockdown of VASH1-induced differentially expressed genes in HUVEcs were greatly enriched in the Wnt signaling pathway (DAAM1, LEF1, RAC2, FRAT1, NFATc2 and WNT5A). Together, these data suggested that ZNF667 facilitates myocardial ischemia-driven angiogenesis through transcriptional repression of VASH1 and regulation of Wnt signaling pathway.