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NO-H2S interactions involve cGMP


Hydrogen sulfide (H2S) and nitric oxide (NO) have been recognized as endogenous signaling molecules, involved in a variety of homeostatic and disease processes. Although it is well-established that NO increases cGMP content of cells and tissues by activating soluble guanylyl cyclase (sGC), the ability of H2S to affect cyclic nucleotides levels has been controversial.


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.


Inhibition of the production of one gasotransmitter (NO or H2S) reduces the ability of the other to elevate cGMP and to trigger angiogenesis and vasodilation. These observations establish the existence of a positive, synergistic cross-talk between H2S and NO in vascular tissues.


Much of the above-mentioned work has been done through collaborative efforts in the context of the European Network of Gasotransmitters (COST-BM1005) that is funded through the European Science Foundation.

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Correspondence to Andreas Papapetropoulos.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Papapetropoulos, A. NO-H2S interactions involve cGMP. BMC Pharmacol Toxicol 14 (Suppl 1), O32 (2013).

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