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

Cyclooxygenasel (COX1) and COX2 mediate the rate-limiting step in arachidonic acid metabolism. Expression of COX2 mRNA and protein is often enhanced in various human cell types by inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα). IL-1β enhanced expression 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 receptors) 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 induced 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.