Vascular endothelial growth factor is a neurotrophic factor which stimulates axonal outgrowth through the flk-1 receptor

Vascular endothelial growth factor (VEGF) is an angiogenic factor that stim ulates axonal outgrowth. Here we used in situ hybridization and immunocytoc hemistry to study the VEGF receptor flk-1 in cultured superior cervical gan glia (SCG) and dorsal root ganglia (DRG) from adult mice, and also the effe cts of VEGF on regeneration in vitro. Neurons in both ganglia contained the flk-1 receptor and showed an increased mRNA expression and immunoreactivit y for flk-1 after 48 h in culture. In SCG, but not in DRG, double immunosta ining for flk-1 and VEGF revealed coexpression in many neurons, implying th at VEGF may exert both autocrine and paracrine actions. One proportion of t he flk-1-positive neurons in DRG stained positive for the large neuron mark er RT97 and another proportion expressed calcitonin gene-related peptide (C GRP). Small IB4-positive neurons were devoid of flk-1 immunoreactivity. Mos t flk-1-positive neurons in the DRG, but not in the SCG, were also immunore active to neuropilin-1. VEGF was found to stimulate axonal outgrowth from D RG, both by an action on the growing axons and the nerve cell bodies. The l atter effect could be mediated by retrograde axonal transport as revealed b y the use of a two compartment system to assay axonal outgrowth. We also fo und that the VEGF-induced axonal outgrowth was blocked by the flk-1 inhibit or SU5416. The results strongly suggest that VEGF acts as a neurotrophic fa ctor and plays an important role during the regeneration of peripheral nerv es.