Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation

摘要

Hydrogen sulfide (H_2S) is a unique gasotransmitter, with regulatory roles in the cardiovascular, nervous, and immune systems. Some of the vascular actions of H_2S (stimulation of angiogenesis, relaxation of vascular smooth muscle) resemble those of nitric oxide (NO). Although it was generally assumed that H_2S and NO exert their effects via separate pathways, the results of the current study show that H_2S and NO are mutually required to elicit angiogenesis and vasodilatation. Exposure of endothelial cells to H_2S increases intracellular cyclic guanosine 5-monophosphate (cGMP) in a NO-dependent manner, and activated protein kinase G (PKG) and its downstream effector, the vasodilator-stimulated phospho-protein (VASP). Inhibition of endothelial isoform of NO synthase (eNOS) or PKG-I abolishes the H_2S-stimulated angiogenic response, and attenuated H_2S-stimulated vasorelaxation, demonstrating the requirement of NO in vascular H_2S signaling. Conversely, silencing of the H_2S-producing enzyme cystathionine-y-lyase abolishes NO-stimulated cGMP accumulation and angiogenesis and attenuates the acetylcholine-induced vasorelaxation, indicating a partial requirement of H2S in the vascular activity of NO. The actions of H_2S and NO converge at cGMP; though H_2S does not directly activate soluble guanylyl cyclase, it maintains a tonic inhibitory effect on PDE5, thereby delaying the degradation of cGMP. H2S also activates PI3K/Akt, and increases eNOS phosphorylation at its activating site S1177. The cooperative action of the two gasotransmitters on increasing and maintaining intracellular cGMP is essential for PKG activation and angiogenesis and vasorelaxation. H_2S-induced wound healing and microvessel growth in matrigel plugs is suppressed by pharmacological inhibition or genetic ablation of eNOS. Thus, NO and H_2S are mutually required for the physiological control of vascular function.