Vascular endothelial growth factor regulates adult hippocampal cell proliferation through MEK/ERK- and PI3K/Akt-dependent signaling
- Vascular endothelial growth factor regulates adult hippocampal cell proliferation through MEK/ERK- and PI3K/Akt-dependent signaling
- Neil M. Fournier; 이보영; Mounira Banasr; Maha Elsayed; Ronald Duman
- VEGF; Neurotrophic factors; MEK/ERK; PI3K/AKT; Fluoxetine; Neurogenesis; Hippocampus
- Issue Date
- VOL 63, NO 4, 642-652
- 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 BrdUlabeled
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 o
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