H2O2-induced microvessel barrier dysfunction: the interplay between reactive oxygen species, nitric oxide, and peroxynitrite

Xueping Zhou, Yan Qian, Dong Yuan, Qilong Feng, Pingnian He

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Elevated H2O2 is implicated in many cardiovascular diseases. We previously demonstrated that H2O2-induced endothelial nitric oxide synthase (eNOS) activation and excessive NO production contribute to vascular cell injury and increases in microvessel permeability. However, the mechanisms of excessive NO-mediated vascular injury and hyperpermeability remain unknown. This study aims to examine the functional role of NO-derived peroxynitrite (ONOO) in H2O2-induced vascular barrier dysfunction by elucidating the interrelationships between H2O2-induced NO, superoxide, ONOO, and changes in endothelial [Ca2+]i and microvessel permeability. Experiments were conducted on intact rat mesenteric venules. Microvessel permeability was determined by measuring hydraulic conductivity (Lp). Endothelial [Ca2+]i, NO, and O2 were assessed with fluorescence imaging. Perfusion of vessels with H2O2 (10 µmol/L) induced marked productions of NO and O2 , resulting in extensive protein tyrosine nitration, a biomarker of ONOO. The formation of ONOO was abolished by inhibition of NOS with NG-Methyl-L-arginine. Blocking NO production or scavenging ONOO by uric acid prevented H2O2-induced increases in endothelial [Ca2+]i and Lp. Additionally, the application of exogenous ONOO to microvessels induced delayed and progressive increases in endothelial [Ca2+]i and microvessel Lp, a pattern similar to that observed in H2O2-perfused vessels. Importantly, ONOO caused further activation of eNOS with amplified NO production. We conclude that the augmentation of NO-derived ONOO is essential for H2O2-induced endothelial Ca2+ overload and progressively increased microvessel permeability, which is achieved by self-promoted amplifications of NO-dependent signaling cascades. This novel mechanism provides new insight into the reactive oxygen and/or reactive nitrogen species-mediated vascular dysfunction in cardiovascular diseases.

Original languageEnglish (US)
Article numberPHY214206
JournalPhysiological reports
Volume7
Issue number16
DOIs
StatePublished - 2019

All Science Journal Classification (ASJC) codes

  • Physiology
  • Physiology (medical)

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