Modulation of angiogenesis is effective in a model of rheumatoid arthritis

A feature of rheumatoid arthritis (RA) is prominent hyperplasia of the synovium, which results in an increased distance between the invasive pannus and the existing synovial vasculature. Concomitantly the hyperplastic tissue imposes an augmented metabolic demand on the pre‐existing vasculature. As a consequence the synovium in RA becomes hypoxic, resulting in an increased rate of formation of new blood vessels, to supply nutrients and oxygen. Targeting the vasculature in RA is a potential therapeutic approach in RA. VEGF, a key vascular permeability and angiogenic factor, is expressed in RA. In this study we utilised adenovirus expressing the secreted form of the extracellular domain of the Flt‐1 VEGF receptor (sFlt‐1) to inhibit VEGF in the collagen‐induced arthritis (CIA) model, to determine whether blocking the effects of vegf might be an effective treatment for RA. AdvsFlt‐1, administered intravenously on the first day of arthritis, significantly suppressed CIA. For example, on d 6 of arthritis the mean increase in paw thickness, which reflects oedema, for untreated and null adenovirus‐treated animals was 0.23 ± 0.05 mm and 0.38 ± 0.08, respectively, compared to 0.07 ± 0.05 for AdvsFlt‐1‐treated mice ( P  < 0.001 vs. Adv0‐treated and untreated mice by 2‐way anova ). Western blot analyses revealed the presence of a 100‐kDa band, corresponding to human sFlt‐1, in liver extracts from arthritic mice infected with AdvsFlt‐1 at 24 h but not 72 h after infection. This band was absent in liver extracts from Adv0‐infected mice and all synovial extracts. Measurement of protein levels by ELISA demonstrated the presence of sFlt‐1 in liver, synovium and serum, although levels declined by 72 h post infection. These data suggest efficient but transient expression of sFlt‐1. Sera from adenovirus infected mice were found to contain antiviral antibodies and additionally, sera from AdvsFlt‐1‐infected but not Adv0‐infected mice recognised human recombinant sFlt‐1. These observations demonstrate that adenoviral mediated delivery of human sFlt‐1 leads to transient gene expression and suppression of CIA. This effect is reduced later in the course of disease due to the expression of antiadenovirus as well as antisFlt‐1 antibodies. Future studies will assess the effect of combination treatment, using AdvsFlt‐1 together with anti‐TNF(antibody, to prolong the beneficial effects of VEGF blockade. These results suggest that blocking the pro‐angiogenic and permeability action of VEGF may be beneficial for treatment of RA.