title: Vascular endothelial growth factor regulates adult hippocampal cell proliferation through MEK/ERK- and PI3K/Akt-dependent signaling.
abstract: Vascular endothelial growth factor (VEGF) is a hypoxia-induced angiogenic protein that exhibits a broad range of neurotrophic and neuroprotective effects in the central nervous system. Given that neurogenesis occurs in close proximity to blood vessels, increasing evidence has suggested that VEGF may constitute an important link between neurogenesis and angiogenesis. Although it is known that VEGF can directly stimulate the proliferation of neuronal progenitors, the underlying signaling pathways responsible in this process are not fully understood. Thus, in the present study, we set out to examine the requirement of two downstream targets of the VEGF/Flk-1 signaling network, the phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways, in producing the mitogenic effects of VEGF. Both in vivo and in vitro experiments showed that a single treatment of VEGF activated Erk1/2 and Akt signaling pathways in the adult rat hippocampus and in cultured hippocampal neuronal progenitor cells. This effect was blocked with the VEGF/Flk-1 inhibitor SU5416. Importantly, microinfusion of VEGF into the rat brain also induced pCREB expression in the dentate gyrus and increased the number of BrdU-labeled cells in the dentate subgranular zone. Double immunofluorescence labeling revealed that a large proportion of BrdU-labeled cells expressed activated forms of Flk-1, Erk1/2, and Akt. Interestingly, treatment with the SSRI fluoxetine, which is well known to stimulate neurogenesis and VEGF-signaling, also produced a similar expression pattern of Erk1/2 and Akt in proliferating cells. Finally, pharmacological experiments showed that administration of inhibitors of either MAPK/ERK (U0126) or PI3K (LY294002) blocked VEGF-stimulation of hippocampal cell proliferation in vivo and in vitro. Taken together, our findings demonstrate that the proliferative actions of VEGF require activation of both ERK and Akt signaling cascades and that these intracellular pathways are stimulated almost exclusively in actively proliferating neuronal progenitor cells of the adult hippocampus.
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Abraham Ribicoff Research Facilities, Yale University School of Medicine, New Haven, CT 06508, USA.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Fournier
authors.forename: Boyoung
authors.initials: B
authors.lastname: Lee
authors.forename: Mounira
authors.initials: M
authors.lastname: Banasr
authors.forename: Maha
authors.initials: M
authors.lastname: Elsayed
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Duman
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D009419:Nerve Tissue Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D058539:Phosphatidylinositol 3-Kinase; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt