The axon guidance cues Semaphorins (Semas) regulate both angiogenesis and the immune system. Among them, Sema4A plays an important role in the immune system by inducing T-cell activation and by inhibiting angiogenesis via PlexinD1 receptor. To date remain unclear the role of Sema4A on macrophages function during the angiogenesis and inflammatory processes. To this aim we analyzed Sema4A expression in human macrophages obtained from buffy coats observing increased expression of Sema4A and its receptors PlexinB2 and PlexinD1 after stimulation with inflammatory stimuli such as the TLR ligands LPS and poly I:C. By checking whether exogenous Sema4A was able to affect macrophages motility, we observed that recombinant Sema4A strongly increased macrophages motility. Of note, while a PlexinB2 antibody was unable to block Sema4A-induced migration, the PlexinD1 antibody strongly inhibited the macrophage chemotactic response to Sema4A. Analyzing the effect of Sema4A on the expression of molecules regulating angiogenesis, we observed a significant induction of VEGF-A transcript and protein in Sema4A-treated macrophages. Remarkably, we observed a significant increase of endothelial cells migration in the presence of Sema4A-treated macrophages that was completely abrogated by the VEGF-A blocking antibody bevacizumab. To further assess the effect of Sema4A in inflammation, using a mouse model of thioglycollate-induced peritonitis, we observed a dramatic increase of Sema4A expression in CD68+ cells 48 h after induction. Finally, to study the involvement of Sema4A on angiogenesis, tissue remodeling and inflammation in vivo we employed a cardiac ischemia/reperfusion mouse model. Interestingly we observed a strong increase of Sema4A expression in macrophages recruited in the ischemic injury. We conclude that Sema4A exerts a pro-angiogenic effect by inducing VEGF-A expression in macrophages and by regulating their recruitment and activation in the angiogenic and inflammatory processes.