Inhibition of angiogenesis has been proposed as a novel therapeutic approach to the treatment of chronic inflammatory diseases such as rheumatoid arthritis. We have assessed carrageenan synovitis in male Wistar rats as a potential model of the increased vascular turnover observed in human synovitis. Intra-articular injection of 100 microl of 2% carrageenan in the right knee on Day 0 was followed by acute joint swelling through Day 3 and persistent macrophage infiltration at Day 28. Endothelial cell proliferation and endothelial cell death each peaked during the acute phase and remained elevated during persistent synovitis. Vascular densities were high in normal synovia, decreased during the acute phase, transiently increased at Day 14, and then returned to control values by Day 28. Lower doses of carrageenan, which stimulated acute joint swelling and macrophage infiltration but not endothelial cell proliferation at Day 3, were not associated with persistent macrophage infiltration at Day 28. Intra-articular injection of substance P or vascular endothelial growth factor, angiogenic factors that are present in normal synovia or are up-regulated during inflammation, respectively, each stimulated endothelial cell expression of proliferating cell nuclear antigen. Increased vascular turnover during acute and persistent phases of synovitis may be regulated by different factors and may serve different roles. The late phase (Day 28) of carrageenan synovitis displays similarities with rheumatoid synovitis, in which endothelial cell turnover is persistently increased despite little overall change in vascular density.