Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis
Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis
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DOI：
10.1101/gad.13.3.295
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发表时间：
1999-02-01
影响因子：
10.5
通讯作者：
Klein, R
中科院分区：
文献类型：
--
作者：
Adams, RH;Wilkinson, GA;Klein, R
Eph 受体酪氨酸激酶及其细胞表面结合配体（肝配蛋白）调节发育中大脑中的轴突引导和捆绑，控制细胞迁移和粘附，并帮助形成胚胎模式。在这里，我们报道了两个 ephrinB 配体和三个 EphB 受体在血管网络中表达并调节血管网络的形成。缺乏ephrinB2以及部分EphB2和EphB3受体信号传导缺陷的双突变体的小鼠在胚胎第11.5天（E11.5）之前在子宫内死亡，因为胚胎血管系统的重塑缺陷。我们的表型分析表明 Eph 受体和肝配蛋白在胚胎脉管系统中存在复杂的相互作用和多种功能。动脉上的 ephrinB2 与其静脉上的 EphB 受体之间的相互作用表明在定义动脉和静脉域之间的边界方面发挥着作用。动脉和静脉内皮细胞表达 ephrinB1，静脉和某些动脉表达 EphB3，表明肝配蛋白和 Eph 受体之间的内皮细胞间相互作用并不限于动脉和静脉之间的边界。此外，ephrinB2和EphB2在邻近血管的间充质中表达以及ephB2/ephB3双突变体中的血管缺陷表明内皮细胞和周围间充质细胞之间需要ephrin-Eph信号传导。最后，肝配蛋白 B 配体在体外诱导毛细血管出芽，其效率与血管生成素-1 (Ang1) 和血管内皮生长因子 (VEGF) 相似，证明肝配蛋白在发育中血管系统的重塑中具有刺激作用。
Eph receptor tyrosine kinases and their cell-surface-bound ligands, the ephrins, regulate axon guidance and bundling in the developing brain, control cell migration and adhesion, and help patterning the embryo. Here we report that two ephrinB ligands and three EphB receptors are expressed in and regulate the formation of the vascular network. Mice lacking ephrinB2 and a proportion of double mutants deficient in EphB2 and EphB3 receptor signaling die in utero before embryonic day 11.5 (E11.5) because of defects in the remodeling of the embryonic vascular system. Our phenotypic analysis suggests complex interactions and multiple functions of Eph receptors and ephrins in the embryonic vasculature. Interaction between ephrinB2 on arteries and its EphB receptors on veins suggests a role in defining boundaries between arterial and venous domains. Expression of ephrinB1 by arterial and venous endothelial cells and EphB3 by veins and some arteries indicates that endothelial cell-to-cell interactions between ephrins and Eph receptors are not restricted to the border between arteries and veins. Furthermore, expression of ephrinB2 and EphB2 in mesenchyme adjacent to vessels and vascular defects in ephB2/ephB3 double mutants indicate a requirement for ephrin-Eph signaling between endothelial cells and surrounding mesenchymal cells. Finally, ephrinB ligands induce capillary sprouting in vitro with a similar efficiency as angiopoietin-1 (Ang1) and vascular endothelial growth factor (VEGF), demonstrating a stimulatory role of ephrins in the remodeling of the developing vascular system.