Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation
Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation
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DOI：
10.1073/pnas.1202916109
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发表时间：
2012-06-05
影响因子：
11.1
通讯作者：
Szabo, Csaba
中科院分区：
文献类型：
--
作者：
Coletta, Ciro;Papapetropoulos, Andreas;Szabo, Csaba
硫化氢（H2S）是一种独特的气体递质，在心血管、神经和免疫系统中具有调节作用。H2S的一些血管作用（刺激血管生成，松弛血管平滑肌）类似于一氧化氮（NO）。虽然一般认为H2S和NO通过不同的途径发挥作用，但目前的研究结果表明，H2S和NO在引发血管生成和血管扩张方面是相互需要的。内皮细胞暴露于H2S下，细胞内环鸟苷5′-单磷酸（cGMP）以no依赖的方式增加，激活蛋白激酶G （PKG）及其下游效应物血管扩张剂刺激磷酸化蛋白（VASP）。抑制内皮NO合成酶（eNOS）或PKG-I可消除H2S刺激的血管生成反应，并减弱H2S刺激的血管松弛，表明NO在血管H2S信号传导中的必要性。相反，抑制H2S生成酶半胱硫氨酸- γ -裂解酶可消除NO刺激的cGMP积累和血管生成，并减弱乙酰胆碱诱导的血管松弛，这表明H2S在NO的血管活性中是部分必需的。H2S和NO的作用汇聚于cGMP；H2S虽然不能直接激活可溶性胍基环化酶，但对PDE5保持强直抑制作用，从而延缓cGMP的降解。H2S还激活PI3K/Akt，并增加其激活位点S1177的eNOS磷酸化。这两种气体递质在增加和维持细胞内cGMP方面的协同作用对于PKG的激活、血管生成和血管舒张是必不可少的。h2s诱导的基质塞伤口愈合和微血管生长受到eNOS的药物抑制或基因消融的抑制。因此，NO和H2S在血管功能的生理控制中是相互需要的。
Hydrogen sulfide (H2S) is a unique gasotransmitter, with regulatory roles in the cardiovascular, nervous, and immune systems. Some of the vascular actions of H2S (stimulation of angiogenesis, relaxation of vascular smooth muscle) resemble those of nitric oxide (NO). Although it was generally assumed that H2S and NO exert their effects via separate pathways, the results of the current study show that H2S and NO are mutually required to elicit angiogenesis and vasodilatation. Exposure of endothelial cells to H2S 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 phosphoprotein (VASP). Inhibition of endothelial isoform of NO synthase (eNOS) or PKG-I abolishes the H2S-stimulated angiogenic response, and attenuated H2S-stimulated vasorelaxation, demonstrating the requirement of NO in vascular H2S signaling. Conversely, silencing of the H2S-producing enzyme cystathionine-gamma-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 H2S and NO converge at cGMP; though H2S 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. H2S-induced wound healing and microvessel growth in matrigel plugs is suppressed by pharmacological inhibition or genetic ablation of eNOS. Thus, NO and H2S are mutually required for the physiological control of vascular function.