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.