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

FASEB J. 2004 Feb;18(2):300-10. doi: 10.1096/fj.03-0473com.

Abstract

Cyclooxygenase1 (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-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha). IL-1beta enhanced expression of various prostanoids and this expression was blocked by COX2 selective inhibitors. IL-1beta 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-1beta-induced angiogenesis was blocked by an EP4 antagonist and a TXA2 receptor antagonist. IL-1beta 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-1beta-induced angiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Cell Line
  • Cell Movement / drug effects
  • Cells, Cultured
  • Cornea / metabolism
  • Cyclooxygenase 2
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Inflammation Mediators / pharmacology*
  • Interleukin-1 / pharmacology*
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / genetics
  • Isoenzymes / metabolism*
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Neovascularization, Physiologic / drug effects*
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Prostaglandins / metabolism
  • Prostaglandins / pharmacology
  • Receptors, Prostaglandin E / agonists
  • Receptors, Prostaglandin E / antagonists & inhibitors
  • Receptors, Prostaglandin E / metabolism
  • Receptors, Thromboxane A2, Prostaglandin H2 / agonists
  • Receptors, Thromboxane A2, Prostaglandin H2 / antagonists & inhibitors
  • Receptors, Thromboxane A2, Prostaglandin H2 / metabolism
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vascular Endothelial Growth Factor A / pharmacology

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Inflammation Mediators
  • Interleukin-1
  • Isoenzymes
  • Membrane Proteins
  • Prostaglandins
  • Receptors, Prostaglandin E
  • Receptors, Thromboxane A2, Prostaglandin H2
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Receptors, Vascular Endothelial Growth Factor