We have shown that H2S increases cGMP in both endothelial and smooth muscle cells. However, H2S does not activate sGC or alter NO-induced sGC activity. Interestingly, H2S inhibits phosphodiesterase (PDE) activity; although it reduces PDE activity of several PDE H2S is most effective and potent against PDE-5. IN line with the ability of H2S to increase cellular cGMP, we observed that exposure of cells to H2S leads to activation of cGMP-dependent protein kinase and VASP phosphorylation. As both NO and H2S promote angiogenesis and vasodilation we explored their interactions in the vessel wall in the context of these two biological processes. Inhibition of eNOS or PKG reduced the H2S-stumlated angiogenic properties of endothelial cells, as well as H2S–stimulated vasorelaxation, suggesting a prominent role for cGMP/PKG pathways in H2S signaling. On the other hand, silencing of the H2S-producing enzyme cystathionine-γ-lyase (CSE) reduced NO-stimulated cGMP accumulation, angiogenesis and smooth muscle relaxation, proving that NO requires H2S to manifest its effects. Finally, H2S-induced wound healing and angiogenesis in vivo was suppressed by pharmacological inhibition or genetic ablation of eNOS.