Roles of inducible cyclooxvgenase-2 in angiogenesis and its significance of therapeutic targets

海绵圆盘周围形成的慢性肉芽肿植入大鼠皮下组织，在14天的实验期内血管生成增加。在海绵肉芽肿组织中，COX-1 mRNA组成性表达，COX-2 mRNA与血管内皮生长因子（VEGF）同时随着新生血管的形成而升高。局部注射bFGF可增加COX-2 mRNA的表达，但不影响COX-1 mRNA的表达。吲哚美辛或选择性COX-2抑制剂、NS-398、尼美舒利和JTE-522均可抑制bFGF的血管生成。bFGF可增强肉芽肿组织中VEGF mRNA的表达，NS-398可降低VEGF mRNA的表达。局部注射VEGF反义寡核苷酸可明显抑制bFGF增强的血管生成。这些结果表明，COX-2可能通过pg介导的VEGF表达促进海绵肉芽肿的新生血管形成，COX-2抑制剂可能有助于治疗涉及血管生成的疾病。利用前列腺素（PG）受体敲除小鼠，我们评估了PG在肿瘤相关血管生成和肿瘤生长中的作用，并确定了PG受体参与其中。野生型小鼠（WT）移植的肉瘤-180细胞形成广泛血管生成的肿瘤，环氧化酶(COX)-2特异性抑制剂对血管生成有明显抑制作用，而COX-1特异性抑制剂对血管生成无抑制作用。缺乏EP3 （EP3-/-）的小鼠海绵植入模型的血管生成受到明显抑制，海绵植入物周围血管内皮生长因子（VEGF）的表达降低。此外，植入肿瘤的生长（肉瘤-180，Lewis肺癌）在EP3-/-中明显受到抑制，其中肿瘤相关的血管生成也减少。免疫组化分析显示基质中主要表达vegf的细胞为CD3/Mac-1双阴性成纤维细胞，与WT相比，基质中vegf的表达在EP3-/-中明显降低，说明宿主基质中PGE2-EP3受体信号通路在肿瘤血管生成中的意义。EP3受体拮抗剂可能是一种对恶性肿瘤有效的候选化学预防剂。少

Angiogenesis in chronic glanuloma formed around sponge discs implanted into subcutaneous tissues of rats was increased over a 14-day experimental period. In sponge granuloma, mRNA of COX-1 was constitutively expressed, whereas that of COX-2 was increased with neovascularization in pararell with that of vascular endothelial growth factor (VEGF). Topical injections of bFGF increased the expression of COX-2 mRNA without affecting that of COX-1 mRNA. The angiogenesis with bFGF was inhibited by indomethacin or selective COX-2 inhibitors, NS-398, nimesulide, and JTE-522. The expression of VEGF mRNA in the granuloma was also enhanced by bFGF, and was reduced by NS-398. The enhanced angiogenesis by bFGF was significantly inhibited by topical injections of VEGF anti-sense oligonucleotide. These results suggested that COX-2 may enhance the neovascularization in sponge granuloma by PG-mediated expression of VEGF, and that a COX-2 inhibitor would facilitate the management of conditions involving a … More ngiogenesis. Using prostaglandin (PG) receptor knockout mice, we have evaluated a role of PGs in tumor-associated angiogenesis and tumor growth, and identified PG receptors involved. Sarcoma-180 cells implanted in wild type mice (WT) formed a tumor with extensive angiogenesis, which was greatly suppressed by specific inhibitors for cyclooxygenase(COX)-2 but not for COX-1. Angiogenesis in sponge implantation model, which can mimic tumor-stromal angiogenesis, was markedly suppressed in mice lacking EP3 (EP3-/-) with reduced expression of vascular endothelial growth factor (VEGF) around the sponge implants. Further, implanted tumor growth (sarcoma-180, Lewis lung carcinoma) was markedly suppressed in EP3-/-, in which tumor-associated angiogenesis was also reduced. Immunohistochemical analysis revealed that major VEGF-expressing cells in the stroma were CD3/Mac-1 double-negative fibroblasts, and that VEGF-expression in the stroma was markedly reduced in EP3-/-, compared with WT. These results demonstrate significance of host stromal PGE2-EP3 receptor signaling in tumor angiogenesis. An EP3 receptor antagonist may be a candidate of chemopreventive agents effective for malignant tumors. Less