Hypoxia upregulates a number of genes, regulated by hypoxia-inducible factor (HIF), involved in erythropoiesis, iron metabolism, apoptosis & metastasis, and glycolysis that are important for organ survival under conditions of low PO2. Others control growth and adaptive remodelling of the existing vasculature (angiogenesis). In response to local hypoxia, using limb ischaemia as a surrogate model of peripheral vascular disease (PVD), HIF signalling may be enhanced by preventing its in situ degradation using the peptide dimethyloxalylglycine (DMOG), promoting skeletal muscle angiogenesis [1]. However, when the proximate stimulus is systemic hypoxia, useful for studying diseases such as chronic obstructive pulmonary disease (COPD), angiogenesis is at best modest and unresponsive to DMOG treatment in mice [2]. Other species appear to be pre-adapted to maintain high aerobic activity under hypoxic conditions [3]. Normobaric hypoxia induces angiogenesis on a regional basis, even within apparently homogeneous muscles, such that it can be easily missed [4]. Interestingly, HIF expression may also be increased by mechanical deformation of cells, as seen in muscle overload [5], and an alternate way of overcoming the usually poor angiogenic response in ischaemic muscle is to apply stretch [6]. Thus, systemic and local hypoxia may act differently, or have different thresholds for inducing capillary growth, suggesting alternate therapeutic strategies may be effective according to the origin of the hypoxic challenge.