Ephrin-A1 is up-regulated by hypoxia in cancer cells and promotes angiogenesis of HUVECs through a coordinated cross-talk with eNOS.
Ephrin-A1 is up-regulated by hypoxia in cancer cells and promotes angiogenesis of HUVECs through a coordinated cross-talk with eNOS.
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DOI：
10.1371/journal.pone.0074464
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Shang ZJ
中科院分区：
文献类型：
--
作者：
Song Y;Zhao XP;Song K;Shang ZJ
缺氧、肝配蛋白-A1和内皮一氧化氮合酶（eNOS）已被证明在肿瘤血管生成中发挥关键作用。然而，ephrin-A1如何受缺氧调节以及ephrin-A1是否与eNOS协同调节血管生成仍有待详细解决。在这里，我们证明鳞状细胞癌细胞（SCC-9）中的肝配蛋白-A1，尤其是上清液中的可溶性肝配蛋白-A1在缺氧条件下上调。在肝配蛋白-A1 诱导的血管生成中观察到人脐静脉内皮细胞 (HUVEC) 中一氧化氮 (NO) 的产生增加，而与 eNOS 特异性抑制剂 N-硝基-L-精氨酸甲酯盐酸盐 (L-NAME) 共培养后，一氧化氮 (NO) 产生逆转。 Western blot 分析证实，在 ephrin-A1 刺激的 HUVEC 中，AktSer473 和 eNOSSer1177 的磷酸化均上调，而总 eNOS 表达不变。磷脂酰肌醇 3-激酶 (PI3K) 的特异性抑制剂 LY294002 显着下调 ephrin-A1 诱导的磷酸化 AktSer473 的表达以及 eNOSSer1177 的磷酸化。这些结果揭示了一种可能的新机制，即 ephrin-A1 在肿瘤微环境中受到调节，并通过与 PI3K/Akt 依赖性 eNOS 激活的协调串扰促进血管生成，这可能与正常血管发育和肿瘤新生血管形成有关。
Hypoxia, ephrin-A1 and endothelial nitric oxide synthase (eNOS) have been proved to play critical roles in tumor angiogenesis. However, how ephrin-A1 is regulated by hypoxia and whether ephrin-A1 cooperates with eNOS in modulation of angiogenesis remain to be addressed in details. Here we demonstrated that both ephrin-A1 in squamous cell carcinoma cells (SCC-9) and especially soluble ephrin-A1 in the supernatants were up-regulated under hypoxic condition. An increased nitric oxide (NO) production in human umbilical vein endothelial cells (HUVECs) was observed in ephrin-A1-induced angiogenesis which was reversed after co-culture with eNOS specific inhibitor, N-nitro-L-arginine methyl ester hydrochloride (L-NAME). Western blot analysis confirmed that both phosphorylation of AktSer473 and eNOSSer1177 were up-regulated in ephrin-A1-stimulated HUVECs, with the total eNOS expression unchanged. The specific inhibitor of phosphatidylinositol 3-kinase (PI3K), LY294002, significantly down-regulated ephrin-A1-induced expression of phosphorylated AktSer473 as well as phosphorylation of eNOSSer1177. These results revealed a possible novel mechanism whereby ephrin-A1 is regulated in tumor microenvironment and promotes angiogenesis through a coordinated cross-talk with PI3K/Akt-dependent eNOS activation which may relate to normal vascular development and tumor neovascularization.
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影响因子：
78.5
作者：
Pasquale, Elena B.
通讯作者：
Pasquale, Elena B.
影响因子：
64.8
作者：
Dimmeler, S;Fleming, I;Zeiher, AM
通讯作者：
Zeiher, AM
DOI：
10.1073/pnas.041359198
发表时间：
2001-02-27
影响因子：
11.1
作者：
Fukumura, D;Gohongi, T;Jain, RK
通讯作者：
Jain, RK
影响因子：
4.8
作者：
Cheng, N;Chen, J
通讯作者：
Chen, J
影响因子：
8
作者：
Brantley, DM;Cheng, N;Chen, J
通讯作者：
Chen, J