Jones Christopher A, London Nyall R, Chen Haoyu, Park Kye Won, Sauvaget Dominique, Stockton Rebecca A, Wythe Joshua D, Suh Wonhee, Larrieu-Lahargue Frederic, Mukouyama Yoh-Suke, Lindblom Per, Seth Pankaj, Frias Antonio, Nishiya Naoyuki, Ginsberg Mark H, Gerhardt Holger, Zhang Kang, Li Dean Y
Department of Oncological Sciences, University of Utah, 15 North 2030 East, Salt Lake City, Utah 84112, USA.
Nat Med. 2008 Apr;14(4):448-53. doi: 10.1038/nm1742. Epub 2008 Mar 16.
The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pathfinding by both structures. The Roundabout (Robo) proteins are guidance receptors with well-established functions in the nervous system; however, their role in the mammalian vasculature remains ill defined. Here we show that an endothelial-specific Robo, Robo4, maintains vascular integrity. Activation of Robo4 by Slit2 inhibits vascular endothelial growth factor (VEGF)-165-induced migration, tube formation and permeability in vitro and VEGF-165-stimulated vascular leak in vivo by blocking Src family kinase activation. In mouse models of retinal and choroidal vascular disease, Slit2 inhibited angiogenesis and vascular leak, whereas deletion of Robo4 enhanced these pathologic processes. Our results define a previously unknown function for Robo receptors in stabilizing the vasculature and suggest that activating Robo4 may have broad therapeutic application in diseases characterized by excessive angiogenesis and/or vascular leak.
血管生成芽已被比作生长中的轴突，事实上，许多蛋白质指导这两种结构的路径寻找。Roundabout（Robo）蛋白是在神经系统中具有明确功能的导向受体；然而，它们在哺乳动物脉管系统中的作用仍不明确。在这里，我们表明内皮细胞特异性的Robo，即Robo4，维持血管完整性。Slit2激活Robo4可通过阻断Src家族激酶激活，在体外抑制血管内皮生长因子（VEGF）-165诱导的迁移、管腔形成和通透性，并在体内抑制VEGF-165刺激的血管渗漏。在视网膜和脉络膜血管疾病的小鼠模型中，Slit2抑制血管生成和血管渗漏，而Robo4的缺失则增强了这些病理过程。我们的结果确定了Robo受体在稳定脉管系统方面以前未知的功能，并表明激活Robo4可能在以过度血管生成和/或血管渗漏为特征的疾病中具有广泛的治疗应用。
