Crosstalk between hydrogen sulfide and nitric oxide in endothelial cells

J Cell Mol Med. 2013 Jul;17(7):879-88. doi: 10.1111/jcmm.12077. Epub 2013 Jun 7.


Hydrogen sulfide (H2 S) and nitric oxide (NO) are major gasotransmitters produced in endothelial cells (ECs), contributing to the regulation of vascular contractility and structural integrity. Their interaction at different levels would have a profound impact on angiogenesis. Here, we showed that H2 S and NO stimulated the formation of new microvessels. Incubation of human umbilical vein endothelial cells (HUVECs-926) with NaHS (a H2 S donor) stimulated the phosphorylation of endothelial NO synthase (eNOS) and enhanced NO production. H2 S had little effect on eNOS protein expression in ECs. L-cysteine, a precursor of H2 S, stimulated NO production whereas blockage of the activity of H2 S-generating enzyme, cystathionine gamma-lyase (CSE), inhibited this action. CSE knockdown inhibited, but CSE overexpression increased, NO production as well as EC proliferation. LY294002 (Akt/PI3-K inhibitor) or SB203580 (p38 MAPK inhibitor) abolished the effects of H2 S on eNOS phosphorylation, NO production, cell proliferation and tube formation. Blockade of NO production by eNOS-specific siRNA or nitro-L-arginine methyl ester (L-NAME) reversed, but eNOS overexpression potentiated, the proliferative effect of H2 S on ECs. Our results suggest that H2 S stimulates the phosphorylation of eNOS through a p38 MAPK and Akt-dependent pathway, thus increasing NO production in ECs and vascular tissues and contributing to H2 S-induced angiogenesis.

Keywords: CSE; Cystathionine gamma-lyase; Endothelial cells; Hydrogen sulfide; Nitric oxide; eNOS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation
  • Chromones / pharmacology
  • Collagen / chemistry
  • Cystathionine gamma-Lyase / chemistry*
  • Drug Combinations
  • Endothelial Cells / cytology*
  • Endothelial Cells / metabolism
  • Enzyme Inhibitors / pharmacology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hydrogen Sulfide / chemistry*
  • Laminin / chemistry
  • Microcirculation
  • Morpholines / pharmacology
  • Neovascularization, Pathologic
  • Neovascularization, Physiologic
  • Nitric Oxide / chemistry*
  • Nitric Oxide Synthase Type III / chemistry*
  • Phosphorylation
  • Proteoglycans / chemistry
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Chromones
  • Drug Combinations
  • Enzyme Inhibitors
  • Laminin
  • Morpholines
  • Proteoglycans
  • matrigel
  • Nitric Oxide
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Collagen
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • p38 Mitogen-Activated Protein Kinases
  • Cystathionine gamma-Lyase
  • Hydrogen Sulfide