Oxygen sensors and angiogenesis

Local oxygen tension has a profound effect on the vasculature, which compensates vascular insufficiency through the induction of angiogenesis. An important mediator in this Process is the hypoxia-inducible factor (HIF) complex, which is activated in hypoxic cells and increases transcription of a broad range of genes including angiogenic growth factors such as VEGF HIF is primarily regulated through oxygen-dependent proteasomal destruction of the regulatory subunit, HIF-1alpha or HIF-2alpha. Regulation is through the modification of specific prolines in HIF-alpha chains which are hydroxylated by a recently identified family of enzymes which require molecular oxygen and 2-oxoglutarate as cosubstrates, and iron as a cofactor. Following modification HIF-alpha chains are captured by a ubiquitin ligase E3 complex containing the von Hippel-Lindau (VHL) tumour suppressor protein. The HIF prolyl hydroxylases (PHD enzymes) act as oxygen sensors regulating HIF, and hence angiogenesis. The PFM-HIF-VHL system provides a range of opportunities for therapeutic manipulation.