Vasculopathy and disordered angiogenesis in selected rheumatic diseases: rheumatoid arthritis and systemic sclerosis

Abstract

Angiogenesis is important in the pathogenesis of systemic inflammatory rheumatic diseases, a family of related disorders that includes rheumatoid arthritis and systemic sclerosis. Rheumatoid arthritis is the rheumatic disease in which the role of angiogenesis has been studied most extensively. However, whereas rheumatoid arthritis is characterized by excessive angiogenesis, the situation is not as clear cut in other rheumatic diseases. For example, systemic sclerosis is characterized by reduced capillary density with insufficient angiogenic responses. Results with angiogenesis inhibitors are controversial, and there is--in parallel--a wide range of upregulated angiogenic factors such as vascular endothelial growth factor. Dysregulation of angiogenesis in systemic sclerosis is accompanied by other pathogenic processes, including fibrosis, autoimmunity and vasculopathy. Animal models with at least partial features of the vasculopathy observed in systemic sclerosis include wound healing models, graft versus host disease models and, in particular, the University of California at Davis line 200 chicken model of systemic sclerosis.

Figure 1

Key stages in the process of angiogenesis. This diagram summarizes the steps involved in the formation of new capillary blood vessels. Steps include protease production, endothelial cell migration and proliferation, vascular tube formation, anastomosis of newly formed tubes, synthesis of a new basement membrane and incorporation of pericytes. Reproduced with permission from Lowe et al. Br J Dermatol 1995 ^© Blackwell Publishing [1].

Figure 2

Potential mechanism of action of some adhesion molecules and cytokines involved in angiogenesis in RA. Basic fibroblast growth factor (bFGF) and tumour necrosis factor (TNF)-α act via α_vβ₃ integrin. In contrast, vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β appear to act via increasing protein kinase C (PKC) with subsequent action on α_vβ₅ integrin. Matrix metalloproteinase (MMP)-2 is proteolytically cleaved into a PEX fragment (a noncatalytic MMP fragment with integrin-binding activity) that acts as a negative regulator of angiogenesis. RA, rheumatoid arthritis. Adapted with permission from Koch. Arthritis Rheum 1998 ^© John Wiley & Sons/American College of Rheumatology [71].