Caspase-3 and the regulation of hypoxic neuronal death by vascular endothelial growth factor

K. Jin, X. O. Mao, S. P. Batteur, E. McEachron, A. Leahy, D. A. Greenberg

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135 Scopus citations

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-κB. 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.

Original languageEnglish
Pages (from-to)351-358
Number of pages8
JournalNeuroscience
Volume108
Issue number2
DOIs
StatePublished - 10 Dec 2001

Keywords

  • Caspase-3
  • Hypoxia
  • Neuroprotection
  • Vascular endothelial growth factor

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    Jin, K., Mao, X. O., Batteur, S. P., McEachron, E., Leahy, A., & Greenberg, D. A. (2001). Caspase-3 and the regulation of hypoxic neuronal death by vascular endothelial growth factor. Neuroscience, 108(2), 351-358. https://doi.org/10.1016/S0306-4522(01)00154-3