Hydrogen sulfide, an enhancer of vascular nitric oxide signaling: mechanisms and implications.

Nitric oxide (NO) vascular signaling has long been considered an independent, self-sufficient pathway. However, recent data indicate that the novel gaseous mediator, hydrogen sulfide (H2 S), serves as an essential enhancer of vascular NO signaling. The current article overviews the multiple levels at which this enhancement takes place. The first level of interaction relates to the formation of biologically active hybrid S/N species and the H2 S-induced stimulation of NO release from its various stable "pools" (e.g., nitrite). The next interactions occur on the level of endothelial calcium mobilization and PI3K/Akt signaling, increasing the specific activity of endothelial NO synthase (eNOS). The next level of interaction occurs on eNOS itself; H2 S directly interacts with the enzyme: sulfhydration of critical cysteines stabilizes it in its physiological, dimeric state, thereby optimizing eNOS-derived NO production and minimizing superoxide formation. Yet another level of interaction, further downstream, occurs at the level of soluble guanylate cyclase (sGC): H2 S stabilizes sGC in its NO-responsive, physiological, reduced form. Further downstream, H2 S inhibits the vascular cGMP phosphodiesterase (PDE5), thereby prolonging the biological half-life of cGMP. Finally, H2 S-derived polysulfides directly activate cGMP-dependent protein kinase (PKG). Taken together, H2 S emerges an essential endogenous enhancer of vascular NO signaling, contributing to vasorelaxation and angiogenesis. The functional importance of the H2 S/NO cooperative interactions is highlighted by the fact that H2 S loses many of its beneficial cardiovascular effects when eNOS is inactive.