Premium
Redox‐Mediated Angiogenesis in the Hypoxic Joint of Inflammatory Arthritis
Author(s) -
Biniecka Monika,
Connolly Mary,
Gao Wei,
Ng Chin T.,
Balogh Emese,
Gogarty Martina,
Santos Lelani,
Murphy Evelyn,
Brayden David,
Veale Douglas J.,
Fearon Ursula
Publication year - 2014
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.38822
Subject(s) - angiogenesis , arthritis , inflammation , tumor necrosis factor alpha , vascular endothelial growth factor , cancer research , small interfering rna , hypoxia (environmental) , inflammatory arthritis , medicine , immunology , chemistry , transfection , biochemistry , organic chemistry , oxygen , vegf receptors , gene
Objective Inflammatory arthritis is associated with joint inflammation, synovial tissue proliferation, and degradation of articular cartilage and bone. Angiogenesis is an early and fundamental component of synovial inflammation. Oxygen metabolism is recognized as an important mediator of joint vascular remodeling. The aim of this study was to determine whether in vivo synovial hypoxia (tissue P O 2 [tP O 2 ]) and tumor necrosis factor (TNF) blocking therapy alter synovial vascular expression of NADPH oxidase (NOX) and how this action regulates angiogenic mechanisms. Methods NOX‐2 protein and messenger RNA expression was examined in patients with inflammatory arthritis before and after receiving TNF inhibitor (TNFi) therapy and in mice with collagen‐induced arthritis (CIA). Proangiogenic processes were assessed in human microvascular endothelial cells (HMVECs) following culture with NOX‐2 activators (TNFα and 4‐hydroxynonenal), small interfering RNA (siRNA) for NOX, and the inhibitor diphenyleneiodonium (DPI) under conditions of normoxia or 3% hypoxia. Results We demonstrated significantly increased NOX‐2 expression in the joints of patients with inflammatory arthritis and the joints of mice with CIA as compared to controls. NOX‐2 expression was higher in patients with synovial tP O 2 levels <3% than in those with tP O 2 levels >3% ( P < 0.05), and correlated with in vivo macroscopic/microscopic measures of angiogenesis, such as vascularity and levels of vascular endothelial growth factor, angiopoietin 2, factor VIII, neural cell adhesion molecule, and α‐smooth muscle actin ( P < 0.05 for all). A decrease in NOX‐2 expression was paralleled by an increase in in vivo tP O 2 levels only in those patients who were defined as TNFi responders. In vitro NOX‐2 activators and 3% hypoxia significantly promoted HMVEC migration, angiogenic tube formation, and secretion of proangiogenic mediators, effects that were blocked by siRNA for NOX‐2 or the NOX‐2 inhibitor DPI. Conclusion We demonstrated that hypoxia activates NOX‐2 protein expression, and NOX‐2–induced oxidative stress may be an initiating factor in driving angiogenesis.