Open AccessHydrogen 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
Author(s) -
Bir Shyamal C.,
Kolluru Gopi K.,
McCarthy Paul,
Shen Xinggui,
Pardue Sibile,
Pattillo Christopher B.,
Kevil Christopher G.
Publication year - 2012
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.112.004093
Subject(s) - medicine , vascular endothelial growth factor , arteriogenesis , angiogenesis , nitric oxide synthase , ischemia , xanthine oxidase , vascular remodelling in the embryo , hypoxia (environmental) , hypoxia inducible factors , nitric oxide , endocrinology , pharmacology , biochemistry , biology , chemistry , enzyme , gene , organic chemistry , oxygen , vegf receptors
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. Methods and 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.