Cyclooxygenase 2 is a key enzyme for inflammatory cytokine‐induced angiogenesis

Abstract

Cyclooxygenasel (COX1) and COX2 mediate the rate‐limiting step in arachidonic acid me¬tabolism. Expression of COX2 mRNA and protein is often enhanced in various human cell types by inflam¬matory cytokines such as interleukin‐1β (IL‐1β) and tumor necrosis factor α (TNFα). IL‐1β enhanced ex¬pression of various prostanoids and this expression was blocked by COX2 selective inhibitors. IL‐1β markedly induced angiogenesis in vitro and in vivo, which was significantly inhibited by COX2 selective inhibitors but not by a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor. In contrast, COX2 selective inhibitors only partially blocked VEGF‐induced angiogenesis. EP2, EP4 (prostaglandin E2 recep¬tors) agonists and thromboxane A2 (TXA2) receptor agonists induced angiogenesis in vitro and in vivo; IL‐1β‐induced angiogenesis was blocked by an EP4 antagonist and a TXA2 receptor antagonist. IL‐1β in¬duced much less angiogenesis in cornea of COX2 knockout mice than that of wild‐type mice. This is the first report that COX2 and some prostanoids play a key role in IL‐1β‐induced angiogenesis.—Kuwano, T., Nakao, S., Yamamoto, H., Tsuneyoshi, M., Yamamoto, T., Kuwano, M., Ono, M. Cyclooxygenase 2 is a keyenzyme for inflammatory cytokine‐induced angiogenesis. FASEB J. 18, 300–310 (2004)