Infiltrating immune cells play a key role in regulating angiogenesis through the production and release of a wide range of pro-angiogenic mediators and cytokines. As the AMP-activated protein kinase (AMPK) has been shown to positively regulate angiogenesis, we investigated the effect of deleting the AMPKα2 subunit in myeloid cells (LysM-AMPKα2) on macrophage and neutrophil function as well as on vascular repair. Wild-type and LysM-AMPKα2 mice were subjected to hindlimb ischemia by femoral artery ligation. The recovery of blood flow (laser Doppler), capillary density (immunohistochemistry) and immune cell infiltration (flow cytometry) were determined. To assess the functional role of AMPKα2 in myeloid cells, bone marrow monocytes were differentiated (in M-CSF) and polarized to M1 (IFN-γ and LPS) or M2 (IL-4 and IL-13) macrophages. Polymorphonuclear cells (PMN) from the murine bone marrow were stimulated with LPS (2 hours). Expression levels of cytokines and growth factors were analyzed using quantitative real time PCR. Recovery of blood flow after hindlimb ischemia was significantly impaired (80%) in LysM-AMPKα2 versus the wild-type littermates. In addition, LysM-AMPKα2 mice showed significantly reduced capillary density and decreased myeloid cell infiltration into the ischemic limb. The deletion of the AMPKα2 subunit had no significant effect on the mRNA expression levels of the M1 markers (TNF-α, IL-1β and inducible nitric oxide synthase) in macrophages. The M2 markers (FIZZ-1, arginase and YM-1) as well as VEGF were under basal decreased in macrophages from LysM-AMPKα2 mice. In PMNs deletion of the AMPKα2 resulted after stimulation with LPS in a significant increase in inflammatory markers whereas the expression of stromal cell-derived factor-1 and the metalloproteinase-9 was significantly reduced compared to cells from wild-type littermates. Deletion of the AMPKα2 in the cells of the myeloid lineage almost abolished vascular repair after hindlimb ischemia. These results indicate that the AMPKα2 subunit plays a crucial role in regulating the inflammatory state and angiogenic potential of myeloid cells.