title: Multiple neurotrophic effects of VEGF on cultured neurons.
abstract: A large literature demonstrates the multifunctional nature of vascular endothelial growth factor (VEGF). Though initially characterized as an endothelial cell-specific factor, recent studies reveal that VEGF has numerous effects on diverse cell types in the brain including neurons. The objective of this study is to examine the effects of VEGF in cultured cortical neurons on survival, p38 mitogen-activated protein kinase (p38 MAP kinase) activity, pro- and anti-apoptotic protein expression and on release of neurotrophic and neurotoxic factors. The results show that VEGF dose-dependently enhances the survival of neurons in culture. VEGF decreases active caspase 3 levels and increases expression of the anti-apoptotic protein Bcl-2. VEGF decreases phosphorylated p38 MAP kinase level and activity in cortical neurons. In addition to modulating survival/death pathways in cortical neurons, VEGF also regulates release of proteins that affect neuronal viability. VEGF causes a dose-dependent release of the neurotrophic protein pigment epithelial-derived factor (PEDF), while significantly decreasing release of the neurotoxic protein amyloid beta. The VEGF-mediated decrease in amyloid beta is dependent on a functional Flt-1 receptor and is inhibited by dicoumarol, a multifunctional inhibitor of stress-activated protein kinase (SAPK)/JNK and NFkappaB pathways. Taken together, these data demonstrate that the neurotrophic effects of VEGF are likely mediated directly by increasing survival and decreasing apoptotic proteins and signals as well as indirectly by modulating release of proteins that affect neuronal viability.
authors.affiliation: Garrison Institute on Aging, Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
authors.forename: Alma
authors.initials: A
authors.lastname: Sanchez
authors.forename: Suchin
authors.initials: S
authors.lastname: Wadhwani
authors.forename: Paula
authors.initials: P
authors.lastname: Grammas
mesh_terms: D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D003470:Culture Media / Q000737:chemistry; D001728:Dicumarol / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D003470:Culture Media; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014475:Uncoupling Agents; D042461:Vascular Endothelial Growth Factor A; C075222:amyloid beta-protein (1-42); D001728:Dicumarol; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; C501164:Flt1 protein, rat; D040281:Vascular Endothelial Growth Factor Receptor-1; D048051:p38 Mitogen-Activated Protein Kinases