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

被引：565

作者：

Coletta, Ciro ^{[1
,2
]}

Papapetropoulos, Andreas ^{[1
,2
,3
]}

Erdelyi, Katalin ^{[1
,2
]}

Olah, Gabor ^{[1
,2
]}

Modis, Katalin ^{[1
,2
]}

Panopoulos, Panagiotis ^{[3
]}

Asimakopoulou, Antonia ^{[3
]}

Geroe, Domokos ^{[1
,2
]}

Sharina, Iraida ^{[4
]}

Martin, Emil ^{[4
]}

Szabo, Csaba ^{[1
,2
]}

机构：

[1] Univ Texas Med Branch, Dept Anesthesiol, Galveston, TX 77555 USA

[2] Shriners Burns Hosp Children, Galveston, TX 77555 USA

[3] Univ Patras, Dept Pharm, Mol Pharmacol Lab, Patras 26504, Greece

[4] Univ Texas Med Sch Houston, Dept Internal Med, Div Cardiol, Houston, TX 77030 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2012年 / 109卷 / 23期

基金：

美国国家卫生研究院;

关键词：

SOLUBLE GUANYLYL CYCLASE; GROWTH-FACTOR; H2S; MOLECULE; TARGETS; MODEL;

D O I：

10.1073/pnas.1202916109

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：9161 / 9166

页数：6