Abstract
Recent evidence suggests that cyclooxygenase (COX)-2 is a mediator of angiogenesis, and COX-2 activity is known to be upregulated in the rheumatoid arthritis (RA) synovium. We examined whether mediation of angiogenesis by COX-2 was occuring in cells of the RA synovium and in microvascular endothelial cells (ECs) that are similar to those found in the RA synovium. We demonstrate that rofecoxib, a selective COX-2 inhibitor, acts directly on human dermal microvascular ECs (HMVECs) to inhibit their chemotactic and tube forming ability. Likewise, pretreatment of HMVECs with rofecoxib significantly inhibited their ability to form tubes induced by conditioned media (CM) of activated RA synovial fibroblasts. When RA synovial fibroblasts were pretreated with rofecoxib for 16 h and then stimulated with interleukin (IL)-1beta, their CM induced significantly less HMVEC tube formation when compared with CM from vehicle-treated RA synovial fibroblasts. ELISAs performed on activated RA fibroblast CM for known proangiogenic factors demonstrated a significant reduction in bFGF, in addition to the expected decrease in PGE(2). Our studies suggest that COX-2-induced angiogenic activity is an active mechanism within diseased synovium and may provide an additional rationale for the use of COX-2 inhibitors in RA.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Arthritis, Rheumatoid / enzymology*
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Arthritis, Rheumatoid / pathology
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Cells, Cultured
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Chemotaxis / drug effects
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / pharmacology
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Dinoprostone / metabolism
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Dose-Response Relationship, Drug
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Drug Combinations
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / enzymology
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Endothelium, Vascular / pathology
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Fibroblast Growth Factor 2 / metabolism
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Fibroblasts / drug effects
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Fibroblasts / pathology
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Humans
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Interleukin-1 / pharmacology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism*
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Lactones / pharmacology
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Membrane Proteins
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Microcirculation / drug effects
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Microcirculation / enzymology
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Microcirculation / pathology
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Neovascularization, Pathologic / metabolism*
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Neovascularization, Pathologic / physiopathology
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Prostaglandin-Endoperoxide Synthases / metabolism*
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Skin / blood supply
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Sulfones
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Synovial Membrane / blood supply
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Synovial Membrane / drug effects
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Synovial Membrane / enzymology*
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Synovial Membrane / pathology
Substances
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Drug Combinations
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Interleukin-1
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Isoenzymes
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Lactones
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Membrane Proteins
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Sulfones
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rofecoxib
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Fibroblast Growth Factor 2
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Dinoprostone