Tumor Angiogenesis: Pericytes and Maturation Are Not to Be Ignored

Figure 1

Hypoxia inducible factors (HIFs) and their role in endothelial cell proliferation. HIF-1α is hydroxylated by prolyl hydroxylase domain proteins (PHDs) and degraded in proteasomes under oxygenated conditions. When the oxygen level decreases, PHD activity is reduced, which leads to the accumulation of HIF-1α. Upon formation, the HIF-1α/β complex activates the transcription of numerous genes. Hypoxia and HIF-1α enhance the expression of VEGFR2, which induces DLL4 expression in the tip cell. Furthermore, DLL4 interacts with the Notch intracellular domain and increases its activity, which increases endothelial cell proliferation. Upregulation of HIF-2α due to lower degradation activates the junctional protein vascular endothelial cadherin (VE cadherin). VE cadherin induces a normalized endothelial phenotype by inhibiting VEGF-driven proliferation and upregulating the soluble isoform of the VEGF-trap VEGFR1 [12].