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.

STAT3 Protein Regulates Vascular Smooth Muscle Cell Phenotypic Switch by Interaction with Myocardin

“…VEGF can also increase phospho-ERK and stimulate the ERK1/2 signaling pathway (43,44). A recent study reported 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 (45). Consistent with these observations, our results showed that VEGF could phosphorylate ERK1/2 to activate it in HA-VSMCs (Fig.…”

“…In addition, ERK1/2 signaling is activated via VEGF and plays a role in cell death by oxygen glucose deprivation (44). A single treatment of VEGF activated ERK1/2 and AKT signaling pathways in the adult rat hippocampus and in cultured hippocampal neuronal progenitor cells (45). VEGF increases phospho-ERK and phospho-AKT in phrenic motor neurons.…”

Fine processes of Nestin-GFP–positive radial glia-like stem cells in the adult dentate gyrus ensheathe local synapses and vasculature

“…In addition, blood circulating factors have substantial effects over the process of neurogenesis (79)(80)(81)(82). VEGF is one of these factors (83), and can stimulate neurogenesis (84)(85)(86) and reversibly modulate neuronal plasticity (87). Other blood-derived factors capable of affecting neurogenesis are glucocorticoids, which are necessary for the regulation of neuronal differentiation and migration (88).…”

VEGF-B selectively regenerates injured peripheral neurons and restores sensory and trophic functions

“…The PI3K-Akt pathway has been implicated in VEGF signaling (13,14). To identify potential mechanisms for VEGF-B activity on peripheral nerves, we used a specific PI3K inhibitor and demonstrated that the PI3K pathway is required for VEGFinduced neurite elongation (Fig.…”