Antiangiogenesis signals by endostatin
Antiangiogenesis signals by endostatin
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DOI：
10.1096/fj.99-1083com
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发表时间：
2001-04-01
期刊：
影响因子：
4.8
通讯作者：
Hirata, Y
中科院分区：
文献类型：
--
作者：
Shichiri, M;Hirata, Y
内皮抑素是一种有效的内源性血管生成抑制剂，可诱导小鼠肿瘤消退。内皮抑制素的细胞外受体和导致肿瘤血管床消退的细胞内信号均未被鉴定。我们证明，内皮抑素，而不是血管抑素，在体内动物试验中使用的浓度相当，迅速下调许多基因在指数生长的内皮细胞。这些包括立即早期反应基因、细胞周期相关基因、调节细胞凋亡抑制剂的基因、有丝分裂原活化蛋白激酶、粘着斑激酶、介导内皮生长的G蛋白偶联受体、有丝分裂因子、粘附分子和细胞结构成分。抑制细胞凋亡抑制因子和细胞增殖基因可能对抗血管生成过程的贡献有限，因为内皮抑素既不诱导细胞凋亡，也不诱导生长抑制，除非在降低血清条件下进行研究。相比之下，即使在血清补充条件下，内皮抑素的抗迁移作用也是快速和有效的。内皮抑素引起的基因抑制和迁移停滞只在内皮细胞，最深刻的微血管内皮细胞。通过靶向同源重组获得的c-myc空成纤维细胞与同基因亲本细胞相比显示出减弱的迁移率，而将c-myc基因引入内皮细胞中废除了内皮抑素的抗迁移作用。通过过表达max或mad抑制E-box驱动的转录抑制内皮细胞迁移。因此，快速下调gems内皮抑素既不恢复增殖的内皮细胞的静息状态，也不诱导凋亡，而是有力地抑制内皮细胞迁移部分通过抑制c-myc的表达。
Endostatin is a potent endogenous angiogenesis inhibitor that induces regression of tumors in mice. Neither an extracellular receptor for endostatin nor intracellular signals that result in the regression of tumor vascular beds have been identified. We dem onstrate that endostatin, but not angiostatin, at comparable concentrations to those used in in vivo animal trials, rapidly down-regulates many genes in exponentially growing endothelial cells. These include immediate early response genes, cell cycle-related genes, and genes regulating apoptosis inhibitors, mitogen-activated protein kinases, focal adhesion kinase, G-protein-coupled receptors mediating endothelial growth, a mitogenic factor, adhesion molecules, and cell structure components. Suppression of both apoptosis inhibitors and cell proliferation genes may have a limited contribution to the antiangiogenesis process because endostatin induces neither apoptosis nor growth inhibition, unless studied under reduced serum conditions. In contrast, the antimigratory effect of endostatin was rapid and potent even under serum-supplemented conditions. Endostatin caused gene suppression and migration arrest exclusively in endothelial cells, most profoundly in microvascular endothelial cells. The c-myc null fibroblasts obtained by targeted homologous recombination showed an attenuated migration rate compared with isogenic parental cells, whereas the introduction of the c-myc gene into endothelial cells abrogated the antimigratory effect of endostatin. Inhibition of E-box-driven transcription by overexpressing max or mad suppressed endothelial migration. Thus, rapid down-regulation of gems by endostatin neither restores proliferating endothelial cells to their resting states nor induces apoptosis; rather, it potently inhibits endothelial cell migration partly via suppression of c-myc expression.