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

诱导型环氧合酶2在血管生成中的作用及其治疗靶点的意义

• 批准号: 12470529
• 负责人: MAJIMA Masataka
• 金额: $ 3.07万
• 依托单位: KITASATO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470529/
• 关键词: angiogenesis; granuloma; tumor; prostaglandin E_2; EP3 receptor; vascular endothelial growth factor; COX-1; COX-2; cyclooxygenase; prortag landin; Ep3 Haptor; ungio genesis; Knockout nice; VEGF; ordo Hnelial cell; fibroblast; Prostaglandin

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

在14天的实验期内，植入大鼠皮下组织的海绵盘周围形成的慢性胶质瘤中的血管生成增加。在海绵状肉芽肿中，考克斯-1的mRNA呈组成性表达，而考克斯-2的mRNA随新生血管的增加而增加，与血管内皮生长因子（VEGF）的表达平行。局部注射bFGF可增加考克斯-2 mRNA的表达，但不影响考克斯-1 mRNA的表达。吲哚美辛或选择性考克斯-2抑制剂NS-398、尼美舒利和JTE-522可抑制bFGF诱导的血管生成。VEGF mRNA在肉芽肿中的表达也被bFGF增强，并被NS-398降低。局部注射VEGF反义寡核苷酸可显著抑制bFGF促进的血管生成。这些结果表明，考克斯-2可能通过PG介导的VEGF表达增强海绵肉芽肿中的新生血管形成，并且考克斯-2抑制剂将有助于涉及血管生成的疾病的管理。 ...更多信息 血管生成使用前列腺素（PG）受体敲除小鼠，我们已经评估了前列腺素在肿瘤相关的血管生成和肿瘤生长中的作用，并确定了参与的PG受体。移植到野生型小鼠（WT）中的肉瘤-180细胞形成了具有广泛血管生成的肿瘤，其被环氧合酶（考克斯）-2但不是考克斯-1的特异性抑制剂极大地抑制。海绵植入模型可以模拟肿瘤间质血管生成，在缺乏EP 3（EP 3-/-）的小鼠中血管生成被显著抑制，海绵植入物周围血管内皮生长因子（VEGF）的表达减少。此外，植入的肿瘤生长（肉瘤-180，刘易斯肺癌）在EP 3-/-中被显著抑制，其中肿瘤相关的血管生成也减少。免疫组织化学分析显示，主要VEGF表达细胞在基质中的CD 3/Mac-1双阴性成纤维细胞，和VEGF的表达显着减少，在EP 3-/-，与WT相比。这些结果表明宿主基质PGE 2-EP 3受体信号传导在肿瘤血管生成中的重要性。EP 3受体拮抗剂可能是恶性肿瘤有效的化学预防剂的候选者。少

项目成果

Muramatsu M,Katada J,Hayashi I, 他: "Chymase as a proangiogenic factor.A possible involvement of chymase-angiotensin-dependent pathway in the hamster sponge angiogenesis model."J Biol Chem.. 275・8. 5545-5552 (2000)

Muramatsu M、Katada J、Hayashi I 等人：“食糜酶作为促血管生成因子。仓鼠海绵血管生成模型中可能涉及食糜酶-血管紧张素依赖性途径。J Biol Chem. 275・8。” (2000)

Yamanaka M, Hayashi I, Fujita T, Cha SH, Endou H: "Potassium-induced increase in renal kallikrein secretion is attenuated in dissected renal connecting tubules of young spontaneously hypertensive rats"Int Immunopharmacol. 2(13-14). 1957-1964 (2002)

Yamanaka M、Hayashi I、Fujita T、Cha SH、Endou H：“在年轻自发性高血压大鼠的解剖肾连接小管中，钾诱导的肾激肽释放酶分泌增加减弱”Int Immunopharmacol。

Hayashi I, Amano H, Yoshida S, Kamata K, Kamata M, Inukai M, Fujita T, Kumagai Y, Furudate S, Majima M: "Suppressed angiogenesis in kininogen-deficiencies"Lab Invest. 82(7). 871-880 (2002)

Hayashi I、Amano H、Yoshida S、Kamata K、Kamata M、Inukai M、Fujita T、Kumagai Y、Furudate S、Majima M：“激肽原缺陷中抑制血管生成”实验室投资。

Sakamoto I, Takahashi T, Kakita A, Hayashi I, Majima M, Yamashina S: "Experimental study on hepatic reinnervation after orthotopic liver transplantation in rats"J Hepatol. 37(6). 814-823 (2002)

Sakamoto I、Takahashi T、Kakita A、Hayashi I、Majima M、Yamashina S：“大鼠原位肝移植后肝神经支配的实验研究”J Hepatol。

Katada J, Muramatsu M, Hayashi I, Tsutsumi M, Konishi Y, Majima M: "Significance of vascular endothelial cell growth factor up-regulation mediated via a chymase-angiotensin-dependent pathway during angiogenesis in hamster sponge granulomas"J Pharmacol Exp

Katada J、Muramatsu M、Hayashi I、Tsutsumi M、Konishi Y、Majima M：“仓鼠海绵肉芽肿血管生成过程中血管内皮细胞生长因子上调通过食糜酶-血管紧张素依赖性途径介导的意义”J Pharmacol Exp