Department of Ophthalmology, The Second Hospital of Jilin University, #218 Ziqiang Street, Changchun, Jilin, 130041, China.
Department of Ophthalmology, Shanghai General Hospital, #100 Haining Road, Shanghai, 200080, China.
Biosci Rep. 2019 Jul 10;39(7). doi: 10.1042/BSR20190513. Print 2019 Jul 31.
Roundabout4 (Robo4) is a transmembrane receptor that belongs to the Roundabout (Robo) family of axon guidance molecules. Robo4 is an endothelial-specific receptor that participates in endothelial cell migration, proliferation, and angiogenesis and the maintenance of vasculature homeostasis. The purpose of this review is to summarize and analyze three main mechanisms related to the expression and function of Robo4 during developmental and pathological angiogenesis. In this review, static shear stress and the binding of transcription factors such as E26 transformation-specific variant 2 (ETV2) and Slit3 induce Robo4 expression and activate Robo4 during tissue and organ development. Robo4 interacts with Slit2 or UNC5B to maintain vascular integrity, while a disturbed flow and the expression of transcription factors in inflammatory or neoplastic environments alter Robo4 expression levels, although these changes have uncertain functions. Based on the mechanisms described above, we discuss the aberrant expression of Robo4 in angiogenesis-related diseases and propose antiangiogenic therapies targeting the Robo4 signaling pathway for the treatment of ocular neovascularization lesions and tumors. Finally, although many problems related to Robo4 signaling pathways remain to be resolved, Robo4 is a promising and potentially valuable therapeutic target for treating pathological angiogenesis and developmental defects in angiogenesis.
Roundabout4（Robo4）是一种跨膜受体，属于 Roundabout（Robo）家族的轴突导向分子。Robo4 是一种内皮细胞特异性受体，参与内皮细胞迁移、增殖和血管生成以及血管稳态的维持。本综述的目的是总结和分析与 Robo4 在发育和病理性血管生成过程中的表达和功能相关的三个主要机制。在本综述中，静态切应力和转录因子如 E26 转化特异性变体 2（ETV2）和 Slit3 的结合诱导 Robo4 的表达，并在组织和器官发育过程中激活 Robo4。Robo4 与 Slit2 或 UNC5B 相互作用以维持血管完整性，而紊乱的血流和炎症或肿瘤环境中转录因子的表达改变 Robo4 的表达水平，尽管这些变化的功能不确定。基于上述机制，我们讨论了 Robo4 在与血管生成相关疾病中的异常表达，并提出了针对 Robo4 信号通路的抗血管生成治疗方法，用于治疗眼部新生血管病变和肿瘤。最后，尽管与 Robo4 信号通路相关的许多问题仍有待解决，但 Robo4 是治疗病理性血管生成和血管生成发育缺陷的有前途且有潜在价值的治疗靶点。
