Angiogenesis is important in the proliferation of inflammatory synovial tissue. Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen that is also angiogenic in vivo. We examined the potential role of VEGF in mediating chemotaxis and proliferation of endothelial cells in rheumatoid arthritis (RA) using samples of synovial tissue and synovial fluid from 55 arthritic patients. Synovial fluid VEGF by ELISA was higher in RA synovial fluids (386 +/- 122 ng/ml) (SE) compared with osteoarthritis (OA) synovial fluids (< 0.8 ng/ml) (p < 0.05) or synovial fluids from patients with other arthritides (6.6 +/- 2 ng/ml). In addition to its known mitogenic properties, we found that human rVEGF was chemotactic for HUVECs at concentrations above 0.02 nM. Incubation of RA synovial fluids with neutralizing anti-VEGF resulted in 23 to 66% (mean 53 +/- 4%) inhibition of HUVEC chemotaxis. Conditioned medium from four of five RA synovial tissue explants was mitogenic for bovine adrenal capillary endothelial cells. Anti-VEGF neutralized from 19 to 42% (mean 28 +/- 4%) of this mitogenic activity. To determine the cellular source of VEGF in synovial tissue, we employed immunohistochemistry. VEGF+ cells were rarely (< 1%+) found in normal synovial tissues. In contrast, RA and OA synovial tissues exhibited VEGF+ lining cells (8% and 13%, respectively). A few synovial tissue macrophages were VEGF+ in both RA and OA (5% and 2%, respectively). These results elucidate a newly described function for VEGF as a potent chemotaxin for endothelial cells as well as a role for VEGF in RA-associated endothelial migration and proliferation.

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