Angiogenesis in the inflamed joint

Rheumatoid arthritis (RA) is a chronic systemic disease characterised by an inflammatory erosive synovitis. Early changes in the synovium are marked by neovascularisation, inflammatory cell infiltration, and associated synoviocyte hyperplasia, which produce a pannus of inflammatory vascular tissue. This pannus covers and erodes articular cartilage, eventually leading to joint destruction.

Angiogenesis is a complex, highly regulated physiological process, which in normal adults is restricted to the female reproductive cycle and wound healing. A coordinated sequence of endothelial cell division, selective degradation of vascular basement membranes and surrounding extracellular matrix (ECM) with migration of endothelial cells1 results in new capillary growth from existing vessels. Pathological angiogenesis is now recognised as a fundamental component of pannus development in RA,2 with evidence of both focal endothelial proliferation and apoptosis in the synovium.3

The importance of angiogenesis in providing the vascular network to sustain synovial and immune cell proliferation is confirmed by pharmacological inhibition of angiogenesis, resulting in suppression of arthritis in experimental models.4-7 More recently, specific inhibition of vascular endothelial growth factor (VEGF) by soluble receptor, sflt-1,8 and by anti-VEGF antibody9 has been shown to attenuate collagen induced arthritis in mice, supporting the major role of VEGF in promoting angiogenesis.

Angiogenic growth factors in RA

The initiation of angiogenesis is associated with expression of a number of angiogenic growth factors of which basic fibroblast growth factor-2 (FGF-2) and VEGF are the most potent.10

In RA, high levels of VEGF,11 FGF-1,12FGF-2,13 transforming growth factor β₁(TGFβ₁),14 and hepatocyte growth factor15 are present in synovial fluid (SF) or synovial membrane, secreted by synoviocytes or infiltrating leucocytes. The presence of these angiogenic factors confirms earlier studies showing that SF induces capillary-like structures in endothelial cell cultures.16

VEGF as a primary modulator of RA angiogenesis

We have investigated the control of VEGF production …