ATVB in Focus Oxygen Sensing From Vessel Sprouting to Normalization Role of the Prolyl Hydroxylase Domain Protein/Hypoxia-Inducible Factor Oxygen-Sensing Machinery

Abstract—The accepted model of vessel branching distinguishes several endothelial cell fates. At the forefront of a vessel sprout, “tip cells ” guide the sprouting vessel toward an angiogenic stimulus. Behind the tip, “stalk cells ” proliferate to elongate the vessel branch and create a lumen. In mature vessels, endothelial cells acquire a streamlined shape to optimally conduct blood flow. For this purpose, endothelial cells switch to the “phalanx ” cell fate, which is characterized by quiescent and nonproliferating cells aligned in a tight cobblestonelike layer. Vessel maturation also requires the recruitment of mural cells (ie, smooth muscle cells and pericytes). These cell fates are often altered in pathological conditions, most prominently during the formation of tumor vasculature. Given the essential role of hypoxia as the driving force for initiating angiogenesis, it is not surprising that the hypoxia-sensing machinery controls key steps in physiological and pathological angiogenesis. (Arterioscler Thromb Vasc Biol. 2010;30:2331-2336.) Key Words: angiogenesis hypoxia HIF PHD Angiogenesis is a dynamic process that is tightly regu-lated by oxygen-sensing mechanisms. The prolyl hy-droxylase domain proteins (PHDs) are oxygen-sensing en-zymes that belong to the evolutionarily conserved superfamily of iron-containing 2-oxoglutarate–dependent di-oxygenases. This family consists of 3 PHDs (PHD1–3) and the factor inhibiting hypoxia-inducible factor (HIF) (FIH).1 Under well-oxygenated conditions, PHDs hydroxylate con-served prolyl residues of the HIF- subunits, thereby gener-ating a binding site for the von Hippel–Lindau tumor sup-pressor protein, which targets HIF- for proteosomal degradation. When oxygen levels decrease, the hydroxylation activity of the PHDs is reduced, leading to HIF- accumula-tion. On binding to HIF-, the HIF-/ complex translocates and activates transcription of numerous genes, including those regulating survival, metabolism, and angiogenesis.2 In normoxia, the transcriptional activity of HIF is reduced by hydroxylation of a conserved asparagine residue by FIH.3