Vascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia.
Vascular endothelial growth factor (VEGF) is a hypoxia-inducible angiogenic peptide with recently identified neurotrophic effects. Because some neurotrophic factors can protect neurons from hypoxic or ischemic injury, we investigated the possibility that VEGF has similar neuroprotective properties. In HN33, an immortalized hippocampal neuronal cell line, VEGF reduced cell death associated with an in vitro model of cerebral ischemia: at a maximally effective concentration of 50 ng/ml, VEGF approximately doubled the number of cells surviving after 24 h of hypoxia and glucose deprivation. To investigate the mechanism of neuroprotection by VEGF, the expression of known target receptors for VEGF was measured by Western blotting, which showed that HN33 cells expressed VEGFR-2 receptors and neuropilin-1, but not VEGFR-1 receptors. The neuropilin-1 ligand placenta growth factor-2 failed to reproduce the protective effect of VEGF, pointing to VEGFR-2 as the site of VEGF's neuroprotective action. Two phosphatidylinositol 3'-kinase inhibitors, wortmannin and LY294002, reversed the neuroprotective effect of VEGF, implicating the phosphatidylinositol 3'-kinase/Akt signal transduction system in VEGF-mediated neuroprotection. VEGF also protected primary cultures of rat cerebral cortical neurons from hypoxia and glucose deprivation. We conclude that in addition to its known role as an angiogenic factor, VEGF may exert a direct neuroprotective effect in hypoxic-ischemic injury.
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Buck Center for Research in Aging, P.O. Box 638, Novato, CA 94948-0638, USA.
Mao
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Greenberg
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D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002459:Cell Fusion; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology* / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D007700:Kinetics; D008222:Lymphokines / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D039942:Neuropilin-1; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D008222:Lymphokines; D009025:Morpholines; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D039942:Neuropilin-1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D005947:Glucose; D000077191:Wortmannin