The pathogenic role of angiogenesis in rheumatoid arthritis

Abstract

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.

Keywords: Angiogenesis; Chemokines; Cytokines; Growth factors; Matrix metalloproteinases and adhesion molecules; RA.

Fig. 1. RA angiogenesis is driven by pro-inflammatory cytokines released from the cells in the synovial tissue-lining layer

In response to inflammatory stimuli, RA synovial tissue macrophages and fibroblasts produce pro-inflammatory cytokines that can modulate expression of adhesion molecules, MMPs, chemokines and growth factors which are all important in different stages of angiogenesis. There are several steps involved in angiogenesis; which consist of endothelial cells migration, endothelial cell proliferation into vascular tubules, separation of the newly formed blood vessels that mature and become interconnected to the circulatory system.

Fig. 2. Ligation of TLRs fosters angiogenesis indirectly through induction of pro-inflammatory cytokines and pro-angiogenic factors

Potentially, TLR endogenous ligands can bind to the RA joint macrophages and activate the production of pro-inflammatory factors such as TNF, IL-1β, IL-6, IL-8, IL-18 and MIF. Excessive leukocyte migration in the RA joint increases the oxygen demand resulting in hypoxia and the subsequent accumulation of the hypoxia inducible factor-1α (HIF-1α). The pro-inflammatory cytokines released into the joint space together with the increased intracellular levels of the HIF-1α can then activate the production of pro-angiogenic factors from the RA synovial tissue macrophages, T cells and fibroblasts. The pro-angiogenic factors increase the joint neovascularization process (Angiogenesis) in order to maintain synovitis.

Fig. 3. Differentiation of TH-1 and TH-17 cells can foster RA angiogenesis

In RA joint, IFN-γ and IL-12 drive the polarization of naïve T cells into TH-1 cells that promote angiogenesis indirectly through inducing the production of TNF, IL-8, IL-18, CCL2 and CCL5 by M1 macrophages. Whereas, TGF-β and IL-6 differentiate naïve T cells into TH-17 cells. TH-17 cells can provoke angiogenesis both directly through the production of IL-17 and indirectly by inducing the secretion of pro-angiogenic factors from RA macrophages and fibroblasts. In contrast, inducible T regulatory cells (iTregs) are differentiated from naïve T cells through the effect of TGF-β and IL-2 and release TGF-β and IL-10 that has an inhibitory effect on RA angiogenesis.