title: The role of vascular cell adhesion molecule 1/ very late activation antigen 4 in endothelial progenitor cell recruitment to rheumatoid arthritis synovium.
abstract: OBJECTIVE
  Marrow-derived endothelial progenitor cells (EPCs) are important in the neovascularization that occurs in diverse conditions such as cardiovascular disorders, inflammatory diseases, and neoplasms. In rheumatoid arthritis (RA), synovial neovascularization propels disease by nourishing the inflamed and hyperproliferative synovium. This study was undertaken to investigate the hypothesis that EPCs selectively home to inflamed joint tissue and may perpetuate synovial neovascularization.
  
  
  METHODS
  In a collagen-induced arthritis (CIA) model, neovascularization and EPC accumulation in mouse ankle synovium was measured. In an antibody-induced arthritis model, EPC recruitment to inflamed synovium was evaluated. In a chimeric SCID mouse/human synovial tissue (ST) model, mice were engrafted subcutaneously with human ST, and EPC homing to grafts was assessed 2 days later. EPC adhesion to RA fibroblasts and RA ST was evaluated in vitro.
  
  
  RESULTS
  In mice with CIA, cells bearing EPC markers were significantly increased in peripheral blood and accumulated in inflamed synovial pannus. EPCs were 4-fold more numerous in inflamed synovium from mice with anti-type II collagen antibody-induced arthritis versus controls. In SCID mice, EPC homing to RA ST was 3-fold greater than to normal synovium. Antibody neutralization of vascular cell adhesion molecule 1 (VCAM-1) and its ligand component alpha4 integrin potently inhibited EPC adhesion to RA fibroblasts and RA ST cryosections.
  
  
  CONCLUSIONS
  These data demonstrate the selective recruitment of EPCs to inflamed joint tissue. The VCAM-1/very late activation antigen 4 adhesive system critically mediates EPC adhesion to cultured RA fibroblasts and to RA ST cryosections. These findings provide evidence of a possible role of EPCs in the synovial neovascularization that is critical to RA pathogenesis.
authors.affiliation: University of Michigan Health System, Internal Medicine Department, Ann Arbor, MI 48109-2200, USA. mdsilver@med.umich.edu
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Silverman
authors.forename: Christian S
authors.initials: CS
authors.lastname: Haas
authors.forename: Ali M
authors.initials: AM
authors.lastname: Rad
authors.forename: Ali S
authors.initials: AS
authors.lastname: Arbab
authors.forename: Alisa E
authors.initials: AE
authors.lastname: Koch
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology; D005260:Female; D006801:Humans; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000503:physiopathology; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology; D013583:Synovial Membrane / Q000098:blood supply / Q000473:pathology* / Q000503:physiopathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology*
chemical_list: D039041:Integrin alpha4beta1; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D003094:Collagen