The acute phase protein a2M is elevated during tissue damage, e.g. cardiac infarction and may be involved in the initiation of repair processes. In the present study the effects of a2M on vasculogenesis of mouse embryonic (ES) cells were investigated. a2M dose-dependent increased vasculogenesis of ES cells as evaluated by assessing CD31-positive cell structures. a2M increased NO generation as evaluated by diaminofluorescein diacetate (DAF-DA) microfluorometry, activated extracellular regulated kinase 1/2 (ERK1/2) and PI3-kinase (PI3k), and increased the expression of fibroblast growth factor-2 (FGF-2) but not VEGF or hypoxia-induced factor-1a. The stimulation of vasculogenesis by a2M as well as the increase in FGF-2 expression was abolished in the presence of the ERK1/2 inhibitor PD98059, the PI3k inhibitor LY294002 and the NO-synthase inhibitor L-NAME. Furthermore NO generation was blunted in the presence of L-NAME, LY294002 and PD98059. In summary our data suggest that a2M stimulates vasculogenesis of ES cells by increasing FGF-2 via NO-synthase activation.