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

Ciro Coletta, Andreas Papapetropoulos, Katalin Erdelyi, Gabor Olah, Katalin Modis, Panagiotis Panopoulos, Antonia Asimakopoulou, Domokos Gerö, Iraida Sharina, Emil Martin, Csaba Szabo

Research output: Contribution to journalArticle

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Abstract

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-γ-lyase abolishes NO-stimulated cGMP accumulation and angiogenesis and attenuates the acetylcholine-induced vasorelaxation, indicating a partial requirement of H 2S 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. H 2S-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.

Original languageEnglish (US)
Pages (from-to)9161-9166
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number23
DOIs
StatePublished - Jun 5 2012

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Hydrogen Sulfide
Vasodilation
Endothelium
Nitric Oxide
Guanosine Monophosphate
Water
Cyclic GMP-Dependent Protein Kinases
Blood Vessels
Gasotransmitters
Protein Isoforms
Nitric Oxide Synthase
Cystathionine
Lyases
Nitric Oxide Synthase Type III
Cardiovascular System
Microvessels
Phosphatidylinositol 3-Kinases
Vascular Smooth Muscle
Wound Healing
Nervous System

ASJC Scopus subject areas

  • General

Cite this

Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation. / Coletta, Ciro; Papapetropoulos, Andreas; Erdelyi, Katalin; Olah, Gabor; Modis, Katalin; Panopoulos, Panagiotis; Asimakopoulou, Antonia; Gerö, Domokos; Sharina, Iraida; Martin, Emil; Szabo, Csaba.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 23, 05.06.2012, p. 9161-9166.

Research output: Contribution to journalArticle

Coletta, Ciro ; Papapetropoulos, Andreas ; Erdelyi, Katalin ; Olah, Gabor ; Modis, Katalin ; Panopoulos, Panagiotis ; Asimakopoulou, Antonia ; Gerö, Domokos ; Sharina, Iraida ; Martin, Emil ; Szabo, Csaba. / Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 23. pp. 9161-9166.
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AU - Panopoulos, Panagiotis

AU - Asimakopoulou, Antonia

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AU - Sharina, Iraida

AU - Martin, Emil

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