title: Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation.
abstract: Hydrogen sulfide (H(2)S) is a unique gasotransmitter, with regulatory roles in the cardiovascular, nervous, and immune systems. Some of the vascular actions of H(2)S (stimulation of angiogenesis, relaxation of vascular smooth muscle) resemble those of nitric oxide (NO). Although it was generally assumed that H(2)S and NO exert their effects via separate pathways, the results of the current study show that H(2)S and NO are mutually required to elicit angiogenesis and vasodilatation. Exposure of endothelial cells to H(2)S 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 H(2)S-stimulated angiogenic response, and attenuated H(2)S-stimulated vasorelaxation, demonstrating the requirement of NO in vascular H(2)S signaling. Conversely, silencing of the H(2)S-producing enzyme cystathionine-γ-lyase abolishes NO-stimulated cGMP accumulation and angiogenesis and attenuates the acetylcholine-induced vasorelaxation, indicating a partial requirement of H(2)S in the vascular activity of NO. The actions of H(2)S and NO converge at cGMP; though H(2)S does not directly activate soluble guanylyl cyclase, it maintains a tonic inhibitory effect on PDE5, thereby delaying the degradation of cGMP. H(2)S 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(2)S-induced wound healing and microvessel growth in matrigel plugs is suppressed by pharmacological inhibition or genetic ablation of eNOS. Thus, NO and H(2)S are mutually required for the physiological control of vascular function.
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch and Shriners Burns Hospital for Children, Galveston, TX 77555, USA.
authors.forename: Ciro
authors.initials: C
authors.lastname: Coletta
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
authors.forename: Katalin
authors.initials: K
authors.lastname: Erdelyi
authors.forename: Gabor
authors.initials: G
authors.lastname: Olah
authors.forename: Katalin
authors.initials: K
authors.lastname: Módis
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Panopoulos
authors.forename: Antonia
authors.initials: A
authors.lastname: Asimakopoulou
authors.forename: Domokos
authors.initials: D
authors.lastname: Gerö
authors.forename: Iraida
authors.initials: I
authors.lastname: Sharina
authors.forename: Emil
authors.initials: E
authors.lastname: Martin
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D003094:Collagen; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D004338:Drug Combinations; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006862:Hydrogen Sulfide / Q000378:metabolism / Q000494:pharmacology*; D007797:Laminin; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011509:Proteoglycans; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014945:Wound Healing / Q000187:drug effects; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D004338:Drug Combinations; D007797:Laminin; D008840:Microfilament Proteins; D010750:Phosphoproteins; D011509:Proteoglycans; D000098662:Vasodilator-Stimulated Phosphoprotein; C059485:matrigel; D009569:Nitric Oxide; D003094:Collagen; D052250:Nitric Oxide Synthase Type III; D017869:Cyclic GMP-Dependent Protein Kinases; D003542:Cystathionine gamma-Lyase; D006152:Cyclic GMP; D006862:Hydrogen Sulfide