Cyclo-oxygenase-2 enhances basic fibroblast growth factor-induced angiogenesis through induction of vascular endothelial growth factor in rat sponge implants

Br J Pharmacol. 2000 Jun;130(3):641-9. doi: 10.1038/sj.bjp.0703327.


Angiogenesis is reportedly enhanced by prostaglandins (PGs). In the present study, we investigated whether or not cyclo-oxygenase (COX)-2 mediated angiogenesis in chronic and proliferate granuloma. In rat sponge implants, angiogenesis was gradually developed over a 14-day experimental period as granuloma formed. This angiogenesis was enhanced by topical injections of human recombinant basic fibroblast growth factor (bFGF). In sponge granuloma, mRNA of COX-1 was constitutively expressed, whereas that of COX-2 was increased with neovascularization in parallel with that of vascular endothelial growth factor (VEGF). Topical injections of bFGF increased the expression of COX-2 mRNA. bFGF-stimulated angiogenesis was inhibited by indomethacin or selective COX-2 inhibitors, NS-398, nimesulide, and JTE-522. The levels of PGE(2) and 6-keto-PGF(1alpha) in the sponge granuloma were increased with bFGF 13 fold and 9 fold, respectively, and these levels were markedly reduced by NS-398. The expression of VEGF mRNA in the granuloma was also enhanced by bFGF, and was reduced by NS-398. Topical injections of PGE(2) and beraprost sodium, a PGI(2) analogue, increased the expression of VEGF mRNA, with angiogenesis enhancement. The enhanced angiogenesis by bFGF was significantly inhibited by topical injections of VEGF anti-sense oligonucleotide. These results suggested that COX-2 may enhance bFGF-induced neovascularization in sponge granuloma by PG-mediated expression of VEGF, and that a COX-2 inhibitor would facilitate the management of conditions involving angiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology
  • Endothelial Growth Factors / biosynthesis*
  • Endothelial Growth Factors / genetics
  • Fibroblast Growth Factor 2 / pharmacology*
  • Foreign-Body Reaction / metabolism
  • Foreign-Body Reaction / pathology
  • Granuloma / metabolism
  • Granuloma / pathology
  • Immunohistochemistry
  • Isoenzymes / genetics
  • Isoenzymes / pharmacology*
  • Lymphokines / biosynthesis*
  • Lymphokines / genetics
  • Male
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology*
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / pharmacology*
  • Prostaglandins / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Endothelial Growth Factors
  • Isoenzymes
  • Lymphokines
  • Prostaglandins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Fibroblast Growth Factor 2
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases