Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996-0845, USA.
J Immunol. 2011 Jun 15;186(12):7195-204. doi: 10.4049/jimmunol.1100014. Epub 2011 May 13.
Antiangiogenic molecules exert a feedback control to restrain pathological angiogenesis, which includes physical binding or inhibition of angiogenic signaling in blood vessel endothelial cells. The latter is the case in which Slit2 ligand-dependent activation of the blood vessel endothelial cell receptor roundabout 4 (Robo4) occurs. In this study, we demonstrate that Robo4 receptors are upregulated following HSV infection of the eye on the majority of the new blood vessel endothelial cells that occur in the corneal stroma. However, expression levels of the ligand for Robo4 receptors, Slit2, was not significantly increased during the disease process, and the knockdown of Slit2 gene expression using lentiviral short hairpin RNAs had no effect on the extent of pathological angiogenesis. In contrast, providing additional Slit2 protein by subconjunctival administration resulted in significantly reduced angiogenesis. The Slit2 binding to Robo4 was shown to block the downstream vascular endothelial growth factor signaling molecules Arf 6 and Rac 1 and reduce the antiapoptotic molecule Bcl-xL in blood vessel endothelial cells. Our results indicate that augmenting the host Robo4/Slit2 system could provide a useful therapeutic approach to control pathological angiogenesis associated with HSV induced stromal keratitis.
抗血管生成分子发挥反馈控制作用，抑制病理性血管生成，包括物理结合或抑制血管内皮细胞中的血管生成信号。在后一种情况下，Slit2 配体依赖性激活血管内皮细胞受体 Roundabout 4（Robo4）发生。在这项研究中，我们证明在眼部 HSV 感染后，大多数发生在角膜基质中的新血管内皮细胞上调了 Robo4 受体。然而，Robo4 受体配体 Slit2 的表达水平在疾病过程中没有显著增加，并且使用慢病毒短发夹 RNA 敲低 Slit2 基因表达对病理性血管生成的程度没有影响。相比之下，通过结膜下给药提供额外的 Slit2 蛋白可导致血管生成显著减少。Slit2 与 Robo4 的结合被证明可以阻断下游血管内皮生长因子信号分子 Arf 6 和 Rac 1，并减少血管内皮细胞中的抗凋亡分子 Bcl-xL。我们的结果表明，增强宿主 Robo4/Slit2 系统可能为控制与 HSV 诱导的基质性角膜炎相关的病理性血管生成提供一种有用的治疗方法。
