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

Abstract

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 PGE2 and 6‐keto‐PGF1α 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 PGE2 and beraprost sodium, a PGI2 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. British Journal of Pharmacology (2000) 130, 641–649; doi:

Inhibition of interleukin‐1 but not tumor necrosis factor suppresses neovascularization in rat models of corneal angiogenesis and adjuvant arthritis

“…Significantly, IL-1 induces VEGF expression in cultured fibroblast-like synoviocytes isolated from RA synovial tissue (35,44). Similarly, IL-1, acting via cyclooxygenase 2 (45,46) and nitric oxide (36), also mediates the expression of bFGF. Notwithstanding a conflicting report that IL-1 can inhibit bFGF-induced angiogenesis in a rabbit corneal angiogenesis model (47), the preponderance of evidence, including the data acquired in our corneal angiogenesis model, suggests that IL-1 plays some part in vivo in the induction of angiogenesis by bFGF and VEGF.…”

COX-2/VEGF-Dependent Facilitation of Tumor-Associated Angiogenesis and Tumor Growth in vivo

“…Angiogenesis can be readily quantified by measurement of the hemoglobin content of the sponge-induced granulation tissue together with histologic examination, and the endogenous substances that induce or inhibit angiogenesis are readily determined. Further, the effects of exogenous substances can be investigated on direct injection into the sponge Majima et al, 1997Majima et al, , 2000Muramatsu et al, 2000). Judging from the results shown in Figures 1 and 2, the angiogenesis observed in this model was dependent on COX-2 but not on COX-1, and the growth factor that induced or maintained angiogenesis is VEGF but not EGF, TGF␤, or IL-1 (Fig.…”

“…To test the proangiogenic capacity COX-2 in the stroma, we developed the sponge implantation model in which the granulation tissues developed gradually with very active angiogenesis, and this model may mimic the events during the development of the stroma Majima et al, 1997Majima et al, , 2000Muramatsu et al, 2000). This model possesses several advantages for studies of angiogenesis.…”

“…Sponge disks (thickness, 5 mm; diameter, 1.3 cm) Majima et al, 1997Majima et al, , 2000Muramatsu et al, 2000) were implanted under light ether anesthesia into the subcutaneous tissues of the back of ddy mice. After a fixed number of days, the granulation tissues that had formed around the sponge were taken immediately after death induced by the ip administration of excessive doses of sodium pentobarbital.…”

“…How-ever, the relevance of these in vitro observations to tumorigenesis in vivo remains to be established. For a mechanistic analysis of angiogenesis in vivo, we have developed a sponge implant model, in which a polyurethane sponge disk implanted subcutaneously in rats induces extensive angiogenesis in surrounding proliferative granuloma tissues Majima et al, 1997Majima et al, , 2000Muramatsu et al, 2000). With the use of this model, we have previously shown that angiogenesis occurs both concomitantly with the induction of COX-2 mRNA and is inhibited by administration either of a nonselective NSAID (indomethacin) or of selective COX-2 inhibitors .…”