Recently, we have reported that a vasoactive peptide adrenomedullin promotes angio/arteriogenesis and prevents cognitive decline after chronic cerebral hypoperfusion in mice. Adrenomedullin upregulated brain levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor, although the regulation mechanism needs to be determined. In this study, we showed that VEGF neutralization partially suppressed adrenomedullin-induced neovascularization and cognitive restoration in vivo. In-vitro, adrenomedullin promoted capillary tube formation of the cultured endothelium, whereas VEGF neutralization abolished these effects. Adrenomedullin was found to upregulate VEGF and basic fibroblast growth factor through the adrenomedullin receptor and the phosphatidylinositol 3-kinase pathway. These results suggest that adrenomedullin has potential as therapy for dementia through enhancement of functional vascular growth.