This study showed that a lower level of expression of the oxygen-sensing molecule PHD2 (also known as EGLN1) by macrophages (in Phd2+/− mice) can protect against ischaemic damage to heart and skeletal muscle by increasing the number of collateral arterial vessels at baseline and by 'preconditioning' these vessels for remodelling (arteriogenesis). Phd2+/− macrophages have a gene expression signature similar to that of M2 macrophages (which promote wound healing and angiogenesis) and produce soluble factors that increase the migration and proliferation of smooth muscle cells. This skewing of Phd2+/− macrophages was shown to depend on activation of the canonical nuclear factor-κB pathway, which is negatively regulated by PHD2 at high oxygen concentrations. Therefore, therapeutic inhibition of PHD2 might be used to promote macrophage-mediated collateral vascularization in patients at risk of ischaemia.