title: Caspase-3 and the regulation of hypoxic neuronal death by vascular endothelial growth factor.
abstract: Vascular endothelial growth factor (VEGF) has neurotrophic and neuroprotective as well as angiogenic properties, but the pathways involved in VEGF-mediated neuronal survival have not been identified. We found previously that VEGF protects cultured neural cells from death induced by serum withdrawal or hypoxia via the activation of VEGF-2/fetal liver kinase-1 receptors, phosphatidylinositol 3'-kinase, Akt and nuclear factor-kappa B. We now report that in mouse cortical neuron cultures subjected to hypoxia, the neuroprotective effect of VEGF involves suppression of cell-death pathways mediated by caspase-3. Exposure to hypoxia for 24 h caused the death of 71+/-4% of cultured neurons; this was reduced to 40+/-1% by VEGF (n=3, P<0.005) and to 44+/-1% by the caspase-3 inhibitor benzyloxycarbonyl-DEVD-fluoromethyl ketone (n=3, P<0.005). VEGF inhibited the activation of caspase-3 as measured by the 17-20-kDa caspase-3 cleavage product, and immunolocalization of VEGF and activated caspase-3 showed segregated expression in separate neuronal populations. An antisense, but not sense, oligodeoxyribonucleotide directed against VEGF increased the proportion of neurons expressing activated caspase-3, and correspondingly reduced the viability of hypoxic neurons by 37+/-2% (n=3, P<0.005). These findings suggest that VEGF protects neurons from hypoxic injury by inhibiting the activation of caspase-3, and could therefore act as an endogenous neuroprotective factor in cerebral ischemia.
authors.affiliation: Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: K
authors.initials: K
authors.lastname: Jin
authors.forename: X O
authors.initials: XO
authors.lastname: Mao
authors.forename: S P
authors.initials: SP
authors.lastname: Batteur
authors.forename: E
authors.initials: E
authors.lastname: McEachron
authors.forename: A
authors.initials: A
authors.lastname: Leahy
authors.forename: D A
authors.initials: DA
authors.lastname: Greenberg
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000201:enzymology / Q000503:physiopathology; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D002534:Hypoxia, Brain / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D007150:Immunohistochemistry; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D061945:Caspase Inhibitors; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D008222:Lymphokines; D018696:Neuroprotective Agents; D020319:Oligodeoxyribonucleotides, Antisense; D009842:Oligopeptides; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases