Epoxyeicosatrienoic acids (EETs) are formed from the metabolism of arachidonic acid by cytochrome P450s. EETs promote angiogenesis linked to tumor growth in various cancer models that is attenuated in vivo by cyclooxygenase 2 (COX-2) inhibitors. This study further defines a role for COX-2 in mediating endothelial EET metabolism promoting angiogenesis. Using human aortic endothelial cells (HAECs), we quantified 8,9-EET-induced tube formation and cell migration as indicators of angiogenic potential in the presence and absence of a COX-2 inducer [phorbol 12,13-dibutyrate (PDBu)]. The angiogenic response to 8,9-EET in the presence of PDBu was 3-fold that elicited by 8,9-EET stabilized with a soluble epoxide hydrolase inhibitor (t-TUCB). Contributing to this response was the COX-2 metabolite of 8,9-EET, the 11-hydroxy-8,9-EET (8,9,11-EHET), which exogenously enhanced angiogenic responses in HAECs at levels comparable to those elicited by vascular endothelial growth factor (VEGF). In contrast, the 15-hydroxy-8,9-EET isomer was also formed but inactive. The 8,9,11-EHET also promoted expression of the VEGF family of tyrosine kinase receptors. These results indicate that 8,9-EET-stimulated angiogenesis is enhanced by COX-2 metabolism in the endothelium through the formation of 8,9,11-EHET. This alternative pathway for the metabolism of 8,9-EET may be particularly important in regulating angiogenesis under circumstances in which COX-2 is induced, such as in cancer tumor growth and inflammation.

中文翻译：

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环氧二十碳三烯酸 (EET) 刺激的血管生成由 COX-2 形成的环氧羟基二十碳三烯酸 (EHET) 介导。

环氧二十碳三烯酸 (EET) 是由细胞色素 P450 对花生四烯酸的代谢形成的。EET 促进与各种癌症模型中的肿瘤生长相关的血管生成，在体内被环氧合酶 2 (COX-2) 抑制剂减弱。该研究进一步确定了 COX-2 在介导内皮 EET 代谢促进血管生成中的作用。使用人主动脉内皮细胞 (HAEC)，我们将 8,9-EET 诱导的管形成和细胞迁移量化为存在和不存在 COX-2 诱导剂 [佛波醇 12,13-二丁酸 (PDBu)] 时血管生成潜力的指标. 在 PDBu 存在下对 8,9-EET 的血管生成反应是用可溶性环氧化物水解酶抑制剂稳定的 8,9-EET 引发的 3 倍 ( t-TUCB）。促成这种反应的是 8,9-EET 的 COX-2 代谢物，即 11-羟基-8,9-EET (8,9,11-EHET)，它外源增强 HAEC 中的血管生成反应，其水平与引发的反应水平相当通过血管内皮生长因子（VEGF）。相反，也形成了 15-羟基-8,9-EET 异构体，但没有活性。8,9,11-EHET 还促进酪氨酸激酶受体 VEGF 家族的表达。这些结果表明，通过形成 8,9,11-EHET，内皮中的 COX-2 代谢增强了 8,9-EET 刺激的血管生成。在 COX-2 被诱导的情况下，例如在癌症肿瘤生长和炎症中，这种 8,9-EET 代谢的替代途径在调节血管生成方面可能特别重要。