We sought to identify an essential component of the TEAD4/VGLL4 transcription factor complex that controls vascular endothelial growth factor A (VEGFA) expression in muscle. A yeast 2-hybrid screen was used to clone a novel component of the TEAD4 complex from a human heart cDNA library. We identified interferon response factor 2 binding protein 2 (IRF2BP2) and confirmed its presence in the TEAD4/VGLL4 complex in vivo by coimmunoprecipitation and mammalian 2-hybrid assays. Coexpression of IRF2BP2 with TEAD4/VGLL4 or TEAD1 alone potently activated, whereas knockdown of IRF2BP2 reduced, VEGFA expression in C(2)C(12) muscle cells. Thus, IRF2BP2 is required to activate VEGFA expression. In mouse embryos, IRF2BP2 was ubiquitously expressed but became progressively enriched in the fetal heart, skeletal muscles, and lung. Northern blot analysis revealed high levels of IRF2BP2 mRNA in adult human heart and skeletal muscles, but immunoblot analysis showed low levels of IRF2BP2 protein in skeletal muscle, indicating post-transcriptional regulation of IRF2BP2 expression. IRF2BP2 protein levels are markedly increased by ischemia in skeletal and cardiac muscle compared to normoxic controls. IRF2BP2 is a novel ischemia-induced coactivator of VEGFA expression that may contribute to revascularization of ischemic cardiac and skeletal muscles.