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Fig. 2. Hypoxia-induced neuronal protection mechanisms in the central nervous
system. Tissue hypoxia and cerebral ischaemia activate hypoxia-inducible
factor-1 (HIF-1), which in turn activates gene transcription of a variety of
oxygen-regulated factors, among them erythropoietin (EPO) and vascular
endothelial growth factor (VEGF). These factors, as well as HIF-1 itself,
might also be activated by hypoxia-independent stimuli such as growth factors
or cytokines. EPO and VEGF then confer cellular protection. The main target
for EPO (indicated by a thicker arrow) is neurones, while VEGF mainly prevents
apoptosis and stimulates proliferation of endothelial cells, resulting in new
vessel growth (angiogenesis) and ultimately better oxygenation of hypoxic
tissues. However, to a lesser extent, EPO also contributes to endothelial cell
proliferation, and VEGF is also a direct neuroprotective factor (indicated by
thinner arrows). In addition, both EPO and VEGF also have neurotrophic
properties. Finally, as receptors for both EPO and VEGF are expressed on
microglial cells and astrocytes, glial cells might be a target for both
factors, although the effects on these cells are less clear (indicated by
broken arrows) and the contribution to neuronal survival remains to be
established.
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