Oxygen: the link between vessels and metabolism

Blood vessels carry oxygen to distant tissues. Thus, in the presence of sufficient oxygen (one of the molecules, whose reduction provides the largest free energy per electron transfer), cells will preferrably generate energy via oxidative mechanism. It is therefore not surprising that common signals have developed during evolution to control both oxygen supply (via angiogenesis) and oxidative metabolism. One of the key pathways, shared by both biological processes, is the hypoxia signaling pathway.

This pathway involves the hypoxia inducible transcription factors (HIFs), that induce transcription of target genes regulating angiogenesis and anaerobic metabolism. The activity of the HIFs is, on their turn, regulated by the oxygen-sensing prolyl hydroxylases (PHD), that, via hydroxylation, target the HIFs to proteosomal degradation in normoxia. In the last decade, we have studied the role of HIF-1 and HIF-2 extensively, using mouse genetics and functional genomics, in various processes, including cancer, pulmonary development and angiogenesis.

Our current interest is focused on understanding the role of the three PHDs (PHD1-3) in health and disease. We therefore generated mice conditionally over- or under-expressing each of these PHDs. An initial knockout and knockdown study discovered a novel role for one of the PHDs in hypoxia tolerance through reprogramming of the metabolism, a finding that we will further translate preclinically. Ongoing studies aim at uncovering the role of these PHDs in other disorders, including cancer, angiogenesis, cardiovascular disease and neurodegeneration.

Peter Carmeliet