Vascular endothelial growth factor rescues hippocampal neurons from glutamate‐induced toxicity: signal transduction cascades

Abstract

Vascular endothelial growth factor (VEGF) is known as a selective endothelial cell mitogen that promotes angiogenesis and increases blood vessel formation in vivo. Here we report that VEGF has protective effects on primary hippocampal neurons against glutamate toxicity by acting on phosphatidylinositol 3‐kinase (PI3‐K)/Akt pathways and mitogen‐activated protein kinase kinase (MEK)/extracellular signal‐regulated kinase (ERK) pathways, operating independently of one another. Decrease in the VEGF's neuroprotective effect resulting from inhibition of either pathway alone was significantly enhanced by simultaneous inhibition of both pathways. However, adenovirus‐mediated expression of either the active form of Akt or of MEK significantly inhibited glutamate‐induced neuronal death. Treatment with antisense ODN against Flk‐1, but not against Flt‐1, blocked the effect of VEGF on the activation of Akt and ERK and glutamate‐induced neuronal death. These findings suggest that VEGF has a protective effect on hippocampal neurons against glutamate‐induced toxicity and that this effect is dependent on PI3‐ K/Akt and MEK/ERK signaling pathways mediated primarily through Flk‐1 receptor.

p38 MAPK as a negative regulator of VEGF/VEGFR2 signaling pathway in serum deprived human SK-N-SH neuroblastoma cells

“…This observation is also consistent with the mechanism of action of SB202190, which inhibits p38 MAPK activity but not kinase phosphorylation [26]. Accordingly, these results implicate p38 MAPK as a negative regulator of VEGF-mediated neuroprotection and are consistent with previous reports with endothelial cells that activated p38 MAPK exerts opposing effects on FGF-2 or VEGF-mediated survival [9,16].…”

“…Evidence suggests that PI3K/Akt and MEK/ERK1/2 are critical downstream effectors of VEGF-mediated neuroprotection [16,25,27]. The fact that the survival induced by p38 inhibition is coincident with increased activation levels of ERK1/2 and Akt through VEGFR2 (Fig.…”

“…In endothelial cells, VEGF signaling through VEGFR2 promoted survival by preventing caspase-3 cleavage and p38 MAPK phosphorylation [25] while p38 MAPK inhibition enhanced ERK1/2 activation by VEGF [9]. In stressed neuronal cells, VEGF signals survival through its cognate receptor VEGFR2 and the downstream activation of the PI3K/Akt and MEK/ERK1/2 pathways [16,27] and by suppressing the activation of caspase-3 [10,16] and p38 MAPK [13]. However, the exact role of p38 MAPK in VEGF-mediated signaling under stressful conditions is unclear since VEGF was shown to stimulate p38 MAPK after brain hypoxia [9] and inhibit its activation after retinal ganglion cell axotomy [13].…”

Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo

“…Recent evidence indicates that VEGF can also act directly on neurons to produce neurotrophic and neuroprotective effects. For example, VEGF stimulates axonal outgrowth and improves the survival of cultured superior cervical and dorsal root ganglion neurons (1,2), enhances the survival of mesencephalic neurons in organotypic explant cultures (3), protects HN33 (mouse hippocampal neuron ϫ neuroblastoma) cells from death induced by serum withdrawal (4), reduces hypoxic death of HN33 cells and cultured cerebral cortical neurons (5), and protects cultured hippocampal neurons from glutamate toxicity (6). Conversely, inhibition of VEGF signaling leads to apoptosis in cortical neuron cultures (7), and deletion of the hypoxiaresponse element from the VEGF promoter causes motorneuron degeneration in mice (8), perhaps because of loss of a direct neurotrophic effect of VEGF.…”

Effect of VEGF Treatment on the Blood-Spinal Cord Barrier Permeability in Experimental Spinal Cord Injury: Dynamic Contrast-Enhanced Magnetic Resonance Imaging

“…Recent studies also indicate that VEGF exerts direct neurotrophic effects ( Jin et al, 2000;Matsuzaki et al, 2001;Facchiano et al, 2002;Svensson et al, 2002), plays a role in axonal growth (Kawakami et al, 1996), and stimulates proliferation of stem cells ( Jin et al, 2002;Zhu et al, 2003). Studies by Bartholdi et al (1997) and Skold et al (2000) have demonstrated that cells within the lesioned spinal cord area are capable of expressing VEGF.…”