The ubiquitous A-kinase anchoring protein (AKAP) 12 is a scaffold for various protein kinases, phosphatases, cyclins and other signalling molecules and interacts with the cytoskeleton. Expression of AKAP12 in astrocytes and tumour cells has been described to negatively regulate angiogenesis by reducing VEGF release and controlling cell cycle progression. However, the role of AKAP12 in the endothelium, a primary target for VEGF, is unknown. We therefore studied the role of AKAP12 in the angiogenic response of endothelial cells to VEGF. In primary human endothelial cells transfected with a control siRNA, 72 hours stimulation with VEGF induced significant proliferation, increasing total cell numbers approximately 2-fold compared to non-stimulated cells (P<0.05). In cells treated with siRNA against AKAP12, no significant VEGF-induced proliferation was observed. In line with the strong reduction in proliferative capacity in AKAP12 deficient cells, AKAP12 siRNA reduced the expression of cyclin D1 (to 40 ± 8%, P < 0.001) that is necessary for cell cycle progression. In addition, in a modified spheroid assay, AKAP12 siRNA severely impeded (by 52%, P < 0.001, Figure 1) the sprouting of endothelial cells in response to VEGF. Moreover in AKAP12^-/- mice, we observed a delay in the recovery of blood flow in the ischemic hindlimb. After complete excision of the iliac artery, perfusion of the paw was restored completely within 3 weeks in wildtype animals, whereas in AKAP12^-/- this process required 4 weeks. Taken together, our data indicate that endothelial AKAP12 expression is essential for VEGF-induced angiogenesis in human endothelial cells. These observations are most likely related to a role for AKAP12 in regulating cell-cycle progression and cytoskeletal changes that has been described in other cell types.