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 antibodyinduced 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 ␣4 integrin potently inhibited EPC adhesion to RA fibroblasts and RA ST cryosections.Conclusion. 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.

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“…It is important to note, that this microvascular expansion is occurring before clinical symptoms appear. Synovial neovascularization creates a direct conduit for the entry into the joint of circulating leukocytes that exacerbate inflammation, and provides nutrients to the hyperproliferative synovium [45].…”

“…This might then lead to increased RA synovial blood vessel formation in pannus, perpetuating chronic inflammatory disease [47]. In collagen induced arthritis Silverman et al [45] observed EPC cells in the inflammatory infiltrate of arthritis joins, whereas they did not detect these cells in the joint lining form control animals. This correlates well with observations that the number of EPC in human RA synovial tissue samples was elevated 25-fold over the number of EPCs localized in normal synovial tissue [45].…”

“…Regulation of EPC function may have to important clinical beneficient effects. In RA the inhibition of neovacularization and in consequence inhibition of expansion of invasive tissue of pannus may be very positive clinically effect [45].…”

“…Actually it is commonly accepted that blood vessels in adult can arise not only during angiogenesis (formation of new capillaries from preexisting vessels), but also be result of Innovative Rheumatologyvasculogenesis (de novo new vessel formation from BM-derived progenitor cells after recruitment of a progenitor subpopulation into blood vessels) [45]. Dernbach et al [48] examined whether EPCs are equipped with an antioxidative defence to provide resistance against oxidative stress occurring in chronic inflamed joints.…”

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“…Several lines of evidence indicate that RA is associated with aberrant and severe vasculogenesis (i.e. the de novo formation of blood vessels) within the inflamed joints (Paleolog, 2009, Grisar et al, 2007, Grisar et al, 2005, Herbrig et al, 2006, Hirohata et al, 2004, Jodon de Villeroche et al, 2010, Ruger et al, 2004, Silverman et al, 2007. One of the first observations of vasculogenesis in RA was the discovery that the synovial fluids from patients with RA contained a low molecular weight vasculogenesis factor apparently identical to that derived from tumours (Brown et al, 1980).…”