Cyclo-oxygenase-2 enhances basic fibroblast growth factor-induced angiogenesis through induction of vascular endothelial growth factor in rat sponge implants.
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.
Majima
M
M
Department of Pharmacology, Kitasato University School of Medicine, Kitasato 1-15-1, Sagamihara, Kanagawa 228-8555, Japan. en3m-mjn@asahi-net.or.jp
Hayashi
I
I
Muramatsu
M
M
Katada
J
J
Yamashina
S
S
Katori
M
M
D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005549:Foreign-Body Reaction / Q000378:metabolism / Q000473:pathology; D006099:Granuloma / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics / Q000494:pharmacology*; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000494:pharmacology*; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016228:Endothelial Growth Factors; D007527:Isoenzymes; D008222:Lymphokines; D011453:Prostaglandins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases