Open AccessInduction of endothelial cell decay‐accelerating factor by vascular endothelial growth factor: A mechanism for cytoprotection against complement‐mediated injury during inflammatory angiogenesis
Author(s) -
Mason Justin C.,
Lidington Elaine A.,
Yarwood Helen,
Lublin Douglas M.,
Haskard Dorian O.
Publication year - 2001
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/1529-0131(200101)44:1<138::aid-anr18>3.0.co;2-g
Subject(s) - decay accelerating factor , angiogenesis , vascular endothelial growth factor , microbiology and biotechnology , mapk/erk pathway , vascular endothelial growth factor a , endothelial stem cell , biology , protein kinase a , growth factor , complement system , cd59 , umbilical vein , cytoprotection , vascular endothelial growth factor b , signal transduction , kinase , receptor , immunology , cancer research , endocrinology , biochemistry , immune system , oxidative stress , in vitro , vegf receptors
Objective Decay‐accelerating factor (DAF) is a widely expressed, multifunctional cell surface protein involved in complement regulation and cell signaling. Previous studies have demonstrated that endothelial cell (EC) DAF is up‐regulated by tumor necrosis factor α and inhibits complement binding. Because vascular endothelial growth factor (VEGF) is cytoprotective to endothelium and is expressed at sites of chronic inflammation, we hypothesized that VEGF may induce DAF expression during inflammatory angiogenesis. Methods Human umbilical vein and dermal microvascular EC were isolated using routine procedures, and the regulation and function of DAF, as well as other complement‐regulatory proteins (membrane cofactor protein and CD59), were analyzed following stimulation with VEGF. Results Incubation of large‐ or small‐vessel EC with VEGF led to increased expression of DAF, with maximal expression after 48–72 hours of stimulation. This effect depended on the activation of protein kinase C (PKC) and required increased steady‐state messenger RNA levels and de novo protein synthesis. Although VEGF‐induced EC proliferation was inhibited by both p38 and p42/44 mitogen‐activated protein kinase (MAPK) antagonists, DAF up‐regulation in response to VEGF was only sensitive to inhibition of p38 MAPK. VEGF‐stimulated EC showed a 60% reduction in C3 deposition following complement activation, and this resulted in a marked reduction in complement‐mediated EC lysis. These protective effects were abolished by anti‐DAF monoclonal antibody 1H4. Conclusion This study confirms the importance of PKC for the regulation of DAF expression by EC and reveals VEGF to be a physiologic agonist for this pathway. The up‐regulation of DAF expression by VEGF may represent an important mechanism for the protection of EC from complement‐mediated injury during angiogenesis in inflammatory rheumatic diseases.