EphA2 receptor tyrosine kinase regulates endothelial cell migration and vascular assembly through phosphoinositide 3-kinase-mediated Rac1 GTPase activation
EphA2 receptor tyrosine kinase regulates endothelial cell migration and vascular assembly through phosphoinositide 3-kinase-mediated Rac1 GTPase activation
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DOI：
10.1242/jcs.01061
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发表时间：
2004-04-15
影响因子：
4
通讯作者：
Chen, J
中科院分区：
文献类型：
--
作者：
Brantley-Sieders, DM;Caughron, J;Chen, J
血管生成对于发育过程中的血管重塑至关重要，并有助于癌症等疾病的发病机制。几种 EphB 类受体酪氨酸激酶的靶向破坏会导致胚胎发生过程中的血管重塑缺陷。然而，EphA 类受体在血管重塑中的作用尚未得到充分表征。我们最近证明，EphA 受体的整体抑制会破坏由肝配蛋白、VEGF 或肿瘤源性信号诱导的内皮迁移，但具体靶点仍未确定。在此，我们报道在两种模型系统（原代牛和鼠肺微血管内皮细胞）中，EphA2 通过磷酸肌醇（PI）3 激酶介导的 Rac1 GTPase 激活来调节内皮细胞组装和迁移。 EphA2 缺陷的内皮细胞无法在体外响应 ephrin-A1 进行血管组装和迁移。 Ephrin-A1 刺激可诱导野生型内皮细胞中 PI3 激酶依赖性的 Rac1 激活，而 EphA2 缺陷细胞在刺激后无法激活 Rac1。显性失活 PI3 激酶或 Rac1 的表达抑制肝配蛋白 A1 诱导的内皮细胞迁移。与体外数据一致，EphA2 缺陷小鼠体内 ephrin-A1 的血管生成反应减弱。此外，EphA2缺陷的内皮细胞在移植到受体小鼠体内时无法在体内组装。这些数据表明 EphA2 是产后血管生成的重要调节因子。
Angiogenesis is critical for vascular remodeling during development and contributes to the pathogenesis of diseases such as cancer. Targeted disruption of several EphB class receptor tyrosine kinases results in vascular remodeling defects during embryogenesis. The role of EphA class receptors in vascular remodeling, however, is not well-characterized. We recently demonstrated that global inhibition of EphA receptors disrupts endothelial migration induced by ephrin, VEGF or tumor-derived signals, though the specific target remained undefined. Here, we report that EphA2 regulates endothelial cell assembly and migration through phosphoinositide (PI) 3-kinase-mediated activation of Rac1 GTPase in two model systems: primary bovine and murine pulmonary microvascular endothelial cells. EphA2-deficient endothelial cells fail to undergo vascular assembly and migration in response to ephrin-A1 in vitro. Ephrin-A1 stimulation induces PI3-kinase-dependent activation of Rac1 in wild-type endothelial cells, whereas EphA2-deficient cells fail to activate Rac1 upon stimulation. Expression of dominant negative PI3-kinase or Rac1 inhibits ephrin-A1-induced endothelial cell migration. Consistent with in vitro data, EphA2-deficient mice show a diminished angiogenic response to ephrin-A1 in vivo. Moreover, EphA2-deficient endothelial cells fail to assemble in vivo when transplanted into recipient mice. These data suggest that EphA2 is an essential regulator of post-natal angiogenesis.