Eicosanoid regulation of angiogenesis: role of endothelial arachidonate 12-lipoxygenase
Eicosanoid regulation of angiogenesis: role of endothelial arachidonate 12-lipoxygenase
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DOI：
10.1182/blood.v95.7.2304.007k23_2304_2311
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发表时间：
2000-04-01
期刊：
影响因子：
20.3
通讯作者：
Honn, KV
中科院分区：
文献类型：
--
作者：
Nie, DT;Tang, KQ;Honn, KV
血管生成是一个多步骤的、高度协调的过程，涉及血管萌发、内皮细胞迁移、增殖、管分化和存活。二十烷酸类化合物是花生四烯酸(AA)的代谢产物，对血管内皮细胞具有很强的生物活性。内皮细胞可以合成多种二十烷类化合物，包括12-脂氧合酶(LOX)产物12(S)-羟基二十碳四烯酸(HETE)，在这里我们证明了内源性12-LOX参与了内皮细胞的血管生成反应。首先，12-LOX抑制剂N-苄基-N-羟基-5-苯基戊酰胺可抑制碱性成纤维细胞生长因子或血管内皮生长因子刺激的内皮细胞增殖；其次，12-LOX抑制剂可阻断血管内皮生长因子诱导的内皮细胞迁移，这种抑制作用可被12(S)-HETE部分逆转。第三，用BHPP预处理血管生成内皮细胞系RV-ECT可显著抑制Matrigel内管状/索状结构的形成。第四，过表达12-LOX可显著刺激细胞迁移和细胞分化。与12-LOX在体外对内皮细胞血管生成反应中的关键作用一致，12-LOX抑制剂BHPP通过Matrigel植入法在体内显著减少了bFGF诱导的血管生成，这些发现表明内皮细胞中的AA代谢，特别是12-LOX途径，在血管生成中发挥关键作用。(血液.2000；95：2304-2311)(C)2000由美国血液学学会。
Angiogenesis, the formation of new capillaries from preexisting blood vessels, is a multistep, highly orchestrated process involving vessel sprouting, endothelial cell migration, proliferation, tube differentiation, and survival. Eicosanoids, arachidonic acid (AA)-derived metabolites, have potent biologic activities on vascular endothelial cells. Endothelial cells can synthesize various eicosanoids, including the 12-lipoxygenase (LOX) product 12(S)-hydroxyeicosatetraenoic acid (HETE), Here we demonstrate that endogenous 12-LOX is involved in endothelial cell angiogenic responses. First, the 12-LOX inhibitor, N-benzyl-N-hydroxy-5-phenylpentanamide (BHPP), reduced endothelial cell proliferation stimulated either by basic fibroblast growth factor (bFGF) or by vascular endothelial growth factor (VEGF), Second, 12-LOX inhibitors blocked VEGF-induced endothelial cell migration, and this blockage could be partially reversed by the addition of 12(S)-HETE. Third, pretreatment of an angiogenic endothelial cell line, RV-ECT, with BHPP significantly inhibited the formation of tubelike/cordlike structures within Matrigel. Fourth, overexpression of 12-LOX in the CD4 endothelial cell line significantly stimulated cell migration and tube differentiation. In agreement with the critical role of 12-LOX in endothelial cell angiogenic responses in vitro, the 12-LOX inhibitor BHPP significantly reduced bFGF-induced angiogenesis in vivo using a Matrigel implantation bioassay, These findings demonstrate that AA metabolism in endothelial cells, especially the 12-LOX pathway, plays a critical role in angiogenesis.(Blood .2000;95:2304-2311) (C) 2000 by The American Society of Hematology.