Induction of endothelial cell decay-accelerating factor by vascular endothelial growth factor: a mechanism for cytoprotection against complement-mediated injury during inflammatory angiogenesis

Arthritis Rheum. 2001 Jan;44(1):138-50. doi: 10.1002/1529-0131(200101)44:1<138::AID-ANR18>3.0.CO;2-G.


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 alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD55 Antigens / biosynthesis*
  • CD55 Antigens / genetics
  • Cell Survival / drug effects
  • Complement System Proteins / pharmacology
  • Cytoprotection / drug effects
  • Cytoprotection / physiology
  • Endothelial Growth Factors / pharmacology*
  • Endothelium, Vascular / chemistry
  • Endothelium, Vascular / cytology*
  • Humans
  • Lymphokines / pharmacology*
  • Male
  • Microcirculation / drug effects
  • Mitogen-Activated Protein Kinases / physiology
  • Neovascularization, Pathologic / prevention & control
  • Protein Kinase C / antagonists & inhibitors
  • RNA, Messenger / metabolism
  • Skin / blood supply
  • Skin / cytology
  • Umbilical Veins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • p38 Mitogen-Activated Protein Kinases


  • CD55 Antigens
  • Endothelial Growth Factors
  • Lymphokines
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Complement System Proteins
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases