期刊
NEUROSCIENCE
卷 108, 期 2, 页码 351-358出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0306-4522(01)00154-3
关键词
vascular endothelial growth factor; neuroprotection; hypoxia; caspase-3
资金
- NINDS NIH HHS [NS 37695, NS 35965] Funding Source: Medline
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS037695, P01NS035965] Funding Source: NIH RePORTER
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-kappaB. 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. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.
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