EphB ligand, ephrinB2, suppresses the VEGF- and angiopoietin-1-induced Ras/mitogen-activated protein kinase pathway in venous endothelial cells
EphB ligand, ephrinB2, suppresses the VEGF- and angiopoietin-1-induced Ras/mitogen-activated protein kinase pathway in venous endothelial cells
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DOI：
10.1096/fj.01-0805fje
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发表时间：
2002-05-01
期刊：
影响因子：
4.8
通讯作者：
Koh, GY
中科院分区：
文献类型：
--
作者：
Kim, I;Ryu, YS;Koh, GY
动-静脉毛细血管界面上内皮细胞中的ewitinB2和EphB4之间的相互作用对胚胎毛细血管的正常形态发生至关重要。然而，在血管内皮细胞中，ewitinB2-EphB的细胞内下游信号转导机制尚不清楚。本研究探讨了EphB激酶在血管内皮生长因子(VEGF)和血管生成素-1(Ang1)诱导的人脐静脉内皮细胞(HUVECs)RAS/MAPK信号转导通路中的作用。逆转录聚合酶链式反应结果表明，人脐静脉内皮细胞表达三种已知与ePhinB2结合的EphB激酶：EphB2、EphB3和EphB4。EPhinB2不仅以时间依赖的方式增加EphB2和EphB4的磷酸化，而且还增加了p120-Ras-GTP酶激活蛋白(p120-RasGAP)对EphB2和EphB4的募集。因此，ewitinB2可抑制血管内皮生长因子和血管紧张素转换酶1诱导的Ras-MAPK活性，而不改变血管内皮生长因子诱导的Flk磷酸化或血管紧张素转换酶1诱导的Tie2磷酸化。此外，ewitinB2抑制了血管内皮生长因子和血管紧张素转换酶1诱导的细胞增殖和/或迁移，这主要是通过RAS/MAPK信号转导通路实现的。根据这些结果，我们认为，通过RAS/MAPK级联信号转导的ePhinB2-EphB，可能通过阻止动-静脉界面的内皮细胞的增殖和迁移，对毛细血管内皮细胞的正常形态形成至关重要。
Interaction between ephrinB2 and EphB4 in endothelial cells at the arterial-venous capillary interface is critical for proper embryonic capillary morphogenesis. However, the intracellular downstream signaling of ephrinB2-EphB in vascular endothelial cells is unknown. This study examined the effect of ephrinB2-induced activation of EphB kinases on vascular endothelial growth factor (VEGF)- and angiopoietin-1 (Ang1)-induced Ras/mitogen-activated protein kinase (MAPK) signaling cascades in human umbilical vein endothelial cells (HUVECs). Reverse transcriptase-polymer chain reaction results showed that HUVECs expressed three kinds of EphB kinases known to bind to ephrinB2: EphB2, EphB3, and EphB4. EphrinB2 not only increased the phosphorylation of EphB2 and EphB4 in a time-dependent manner but also increased recruitment of p120-Ras-GTPase-activating protein (p120-RasGAP) to EphB2 and EphB4. Accordingly, ephrinB2 inhibited VEGF- and Ang1-induced Ras-MAPK activities, whereas ephrinB2 did not alter VEGF-induced Flk phosphorylation or Ang1-induced Tie2 phosphorylation. Furthermore, ephrinB2 suppressed VEGF- and Ang1-induced proliferation and/or migration, which are mediated mainly through Ras/MAPK signaling cascades. From these results, we propose that ephrinB2-EphB, signaling through Ras/MAPK cascade, may be critical for proper morphogenesis of capillary endothelium through the arrest of endothelial cell proliferation and migration at the arterial-venous interface.