title: Hydrogen sulfide stimulates ischemic vascular remodeling through nitric oxide synthase and nitrite reduction activity regulating hypoxia-inducible factor-1α and vascular endothelial growth factor-dependent angiogenesis.
abstract: BACKGROUND
  Hydrogen sulfide (H(2)S) therapy is recognized as a modulator of vascular function during tissue ischemia with the notion of potential interactions of nitric oxide (NO) metabolism. However, little is known about specific biochemical mechanisms or the importance of H(2)S activation of NO metabolism during ischemic tissue vascular remodeling. The goal of this study was to determine the effect of H(2)S on NO metabolism during chronic tissue ischemia and subsequent effects on ischemic vascular remodeling responses.
  
  
  RESULTS
  The unilateral, permanent femoral artery ligation model of hind-limb ischemia was performed in C57BL/6J wild-type and endothelial NO synthase-knockout mice to evaluate exogenous H(2)S effects on NO bioavailability and ischemic revascularization. We found that H(2)S selectively restored chronic ischemic tissue function and viability by enhancing NO production involving both endothelial NO synthase and nitrite reduction mechanisms. Importantly, H(2)S increased ischemic tissue xanthine oxidase activity, hind-limb blood flow, and angiogenesis, which were blunted by the xanthine oxidase inhibitor febuxostat. H(2)S treatment increased ischemic tissue and endothelial cell hypoxia-inducible factor-1α expression and activity and vascular endothelial growth factor protein expression and function in a NO-dependent manner that was required for ischemic vascular remodeling.
  
  
  CONCLUSIONS
  These data demonstrate that H(2)S differentially regulates NO metabolism during chronic tissue ischemia, highlighting novel biochemical pathways to increase NO bioavailability for ischemic vascular remodeling.
authors: Departments of Pathology and Medicine, LSU Health Sciences Center-Shreveport, Shreveport, LA 71130, USA.
authors: Shyamal C
authors: SC
authors: Bir
authors: Gopi K
authors: GK
authors: Kolluru
authors: Paul
authors: P
authors: McCarthy
authors: Xinggui
authors: X
authors: Shen
authors: Sibile
authors: S
authors: Pardue
authors: Christopher B
authors: CB
authors: Pattillo
authors: Christopher G
authors: CG
authors: Kevil
mesh_terms: D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D006862:Hydrogen Sulfide / Q000008:administration & dosage*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects* / Q000378:metabolism; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000187:drug effects*; D009573:Nitrites / Q000378:metabolism*; D012039:Regional Blood Flow; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000378:metabolism; D014969:Xanthine Oxidase
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009573:Nitrites; D042461:Vascular Endothelial Growth Factor A; D019001:Nitric Oxide Synthase; D014969:Xanthine Oxidase; D006862:Hydrogen Sulfide
keywords: angiogenesis; ischemia; nitric oxide; vascular endothelial growth factor; xanthine oxidase