Fig. 4.

From oxygen to HIF and from HIF to oxygen. a A drop in the partial pressure of oxygen results in the inactivation of PHDs and FIH. Consequently the HIF pathway is activated, due respectively to inhibition of proteasomal degradation and a release of the C-TAD activity. b HIF in turn impacts on oxygen homeostasis by a double mechanism touching metabolism (green) and oxygen distribution/angiogenesis (red). HIF increases the glycolytic flux and represses the entrance of pyruvate into the Krebs cycle. The consequence is a decrease in oxygen consumption by mitochondrial respiration. In parallel HIF promotes angiogenesis via stimulation of vascular endothelial growth factor (VEGF), interleukin-A (IL-8) and angiopoitin-2 (Ang-2) leading to endothelial cell stimulation and blood vessel destabilization. In combination, HIF simultaneously increases tissue perfusion and decreases local oxygen consumption, thus promoting oxygen diffusion through hypoxic areas