Endothelial nitric oxide synthase activation leads to dilatory H2O2 production in mouse cerebral arteries

Annick Drouin, Nathalie Thorin-Trescases, Edith Hamel, John R. Falck, Eric Thorin

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


Objective: Hydrogen peroxide (H2O2) produced by the vascular endothelium is a signaling molecule regulating vascular tone. We hypothesized that H2O2 derived from eNOS activity could play a physiological role in endothelium-dependent dilation of mouse cerebral arteries. Methods: Simultaneous endothelium-dependent dilation and fluorescence-associated free radical (DCF-DA) or NO (DAF-2) production were recorded in isolated and pressurized (60 mm Hg) cerebral artery of C57Bl/6 male mice. Results: Without synergism, N-nitro-l-arginine (l-NNA) or the H2O2 scavengers catalase, PEG-catalase and pyruvate reduced (P < 0.05) by 50% the endothelium-dependent dilation induced by acetylcholine (ACh). Simultaneously with the dilation, H2O2 - but not NO - production, sensitive to either l-NNA or catalase, was detected. In cerebral arteries from C57Bl/6·eNOS-/- mice, catalase had no effect on ACh-induced dilation and no H2O2-associated fluorescence was observed. In C57Bl/6 mice, silver diethyldithiocarbamate (DETC), a superoxide dismutase (SOD) inhibitor, but not the specific NO scavenger 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl3-oxide (PTIO), prevented ACh-induced dilation and H2O2 production suggesting that eNOS-derived superoxide is an intermediate in the production of H2O2. The catalase-sensitive ACh-induced dilation was restored by the eNOS cofactor tetrahydrobiopterin (BH4). This reversal was associated with a NO-associated fluorescence sensitive to PTIO but not to catalase. Soluble guanylate cyclase inhibition with 1H-[1,2,4]-oxadiazole-4,3-aquinoxalin-1-one (ODQ) prevented the dilation induced by ACh and by exogenous H2O2. Lastly, l-NNA, PTIO and ODQ - but not DETC, catalase or pyruvate - increased the pressure-dependent myogenic tone, suggesting that eNOS produces NO at rest, but leads to H2O2 during muscarinic stimulation. Conclusion: H2O2-dependent dilation in mouse cerebral arteries appears to be a physiological eNOS-derived mechanism.

Original languageEnglish (US)
Pages (from-to)73-81
Number of pages9
JournalCardiovascular Research
Issue number1
StatePublished - Jan 1 2007


  • Endothelial function
  • Microcirculation
  • Nitric oxide
  • Oxygen radicals

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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