The pathogenic role of angiogenesis in rheumatoid arthritis

Angiogenesis is the formation of new capillaries from pre-existing vasculature, which plays a critical role in the pathogenesis of several inflammatory autoimmune diseases such as rheumatoid arthritis (RA), spondyloarthropathies, psoriasis, systemic lupus erythematosus, systemic sclerosis, and atherosclerosis. In RA, excessive migration of circulating leukocytes into the inflamed joint necessitates formation of new blood vessels to provide nutrients and oxygen to the hypertrophic joint. The dominance of the pro-angiogenic factors over the endogenous angiostatic mediators triggers angiogenesis. In this review article, we highlight the underlying mechanisms by which cells present in the RA synovial tissue are modulated to secrete pro-angiogenic factors. We focus on the significance of pro-angiogenic factors such as growth factors, hypoxia-inducible factors, cytokines, chemokines, matrix metalloproteinases, and adhesion molecules on RA pathogenesis. As pro-angiogenic factors are primarily produced from RA synovial tissue macrophages and fibroblasts, we emphasize the key role of RA synovial tissue lining layer in maintaining synovitis through neovascularization. Lastly, we summarize the specific approaches utilized to target angiogenesis. We conclude that the formation of new blood vessels plays an indispensable role in RA progression. However, since the function of several pro-angiogenic mediators is cross regulated, discovering novel approaches to target multiple cascades or selecting an upstream cascade that impairs the activity of a number of pro-angiogenic factors may provide a promising strategy for RA therapy.