Fig. 6.

Proposed pathways of H₂S and NO interaction. Cooperation between NO and H₂S in angiogenesis (Left) or endothelium-dependent vasorelaxation (Right). Binding of VEGF or acetylcholine to its receptor on the endothelial cell mobilizes intracellular calcium and activates eNOS as well as CSE (two calcium-dependent enzymes), resulting in a simultaneous elevation of intracellular NO and H₂S levels in endothelial cells (in the context of angiogenesis) or in the smooth muscle cell (in the context of vasorelaxation). NO stimulates guanylyl cyclase, whereas endogenously produced H₂S maintains a tonic inhibitory effect on PDE5, thereby delaying the degradation of cGMP and permitting physiological cGMP signaling. These two simultaneous actions ensure that cGMP has a sufficiently long half-life to activate PKG to stimulate PKG-dependent downstream signaling such as ERK1/2 and p38 in the case of angiogenesis and myosin light chain (MLC) phosphatase (via its myosin-binding subunit, MBS), large-conductance calcium- and voltage-activated potassium channels (BK_Ca), and IP₃-R-–associated cG-kinase substrate (IRAG) in the case of smooth muscle relaxation. NO and H₂S are also known to activate K_ATP channels, which are also involved in angiogenesis and endothelium-dependent relaxation.