Cheng Nikki, Brantley Dana M, Liu Hua, Lin Qin, Enriquez Miriam, Gale Nick, Yancopoulos George, Cerretti Douglas Pat, Daniel Thomas O, Chen Jin
Department of Cancer Biology, Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Mol Cancer Res. 2002 Nov;1(1):2-11.
Angiogenesis is a multistep process involving a diverse array of molecular signals. Ligands for receptor tyrosine kinases (RTKs) have emerged as critical mediators of angiogenesis. Three families of ligands, vascular endothelial cell growth factors (VEGFs), angiopoietins, and ephrins, act via RTKs expressed in endothelial cells. Recent evidence indicates that VEGF cooperates with angiopoietins to regulate vascular remodeling and angiogenesis in both embryogenesis and tumor neovascularization. However, the relationship between VEGF and ephrins remains unclear. Here we show that interaction between EphA RTKs and ephrinA ligands is necessary for induction of maximal neovascularization by VEGF. EphA2 RTK is activated by VEGF through induction of ephrinA1 ligand. A soluble EphA2-Fc receptor inhibits VEGF-, but not basic fibroblast growth factor-induced endothelial cell survival, migration, sprouting, and corneal angiogenesis. As an independent, but complementary approach, EphA2 antisense oligonucleotides inhibited endothelial expression of EphA2 receptor and suppressed ephrinA1- and VEGF-induced cell migration. Taken together, these data indicate an essential role for EphA receptor activation in VEGF-dependent angiogenesis and suggest a potential new target for therapeutic intervention in pathogenic angiogenesis.
血管生成是一个涉及多种分子信号的多步骤过程。受体酪氨酸激酶（RTK）的配体已成为血管生成的关键介质。三类配体，即血管内皮细胞生长因子（VEGF）、血管生成素和ephrin，通过内皮细胞中表达的RTK发挥作用。最近的证据表明，VEGF与血管生成素协同作用，在胚胎发育和肿瘤新生血管形成过程中调节血管重塑和血管生成。然而，VEGF与ephrin之间的关系仍不清楚。在这里，我们表明EphA RTK与ephrinA配体之间的相互作用对于VEGF诱导最大程度的新生血管形成是必要的。VEGF通过诱导ephrinA1配体激活EphA2 RTK。可溶性EphA2-Fc受体抑制VEGF诱导的，但不抑制碱性成纤维细胞生长因子诱导的内皮细胞存活、迁移、发芽和角膜血管生成。作为一种独立但互补的方法，EphA2反义寡核苷酸抑制EphA2受体的内皮表达，并抑制ephrinA1和VEGF诱导的细胞迁移。综上所述，这些数据表明EphA受体激活在VEGF依赖性血管生成中起重要作用，并提示在病理性血管生成中进行治疗干预的潜在新靶点。
