Uemura Akiyoshi, Fukushima Yoko
Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Osaka 564-8565, Japan.
Int J Mol Sci. 2021 Apr 1;22(7):3684. doi: 10.3390/ijms22073684.
The Rho family of small GTPases (Rho GTPases) act as molecular switches that transduce extrinsic stimuli into cytoskeletal rearrangements. In vascular endothelial cells (ECs), Cdc42, Rac1, and RhoA control cell migration and cell-cell junctions downstream of angiogenic and inflammatory cytokines, thereby regulating vascular formation and permeability. While these Rho GTPases are broadly expressed in various types of cells, RhoJ is enriched in angiogenic ECs. Semaphorin 3E (Sema3E) releases RhoJ from the intracellular domain of PlexinD1, by which RhoJ induces actin depolymerization through competition with Cdc42 for their common effector proteins. RhoJ further mediates the Sema3E-induced association of PlexinD1 with vascular endothelial growth factor receptor (VEGFR) 2 and the activation of p38. Upon stimulation with VEGF-A, RhoJ facilitates the formation of a holoreceptor complex comprising VEGFR2, PlexinD1, and neuropilin-1, leading to the prevention of VEGFR2 degradation and the maintenance of intracellular signal transduction. These pleiotropic roles of RhoJ are required for directional EC migration in retinal angiogenesis. This review highlights the latest insights regarding Rho GTPases in the field of vascular biology, as it will be informative to consider their potential as targets for the treatment of aberrant angiogenesis and hyperpermeability in retinal vascular diseases.
小GTP酶的Rho家族（Rho GTP酶）作为分子开关，将外部刺激转化为细胞骨架重排。在血管内皮细胞（ECs）中，Cdc42、Rac1和RhoA在血管生成和炎性细胞因子下游控制细胞迁移和细胞间连接，从而调节血管形成和通透性。虽然这些Rho GTP酶在各种类型的细胞中广泛表达，但RhoJ在血管生成的ECs中富集。信号素3E（Sema3E）从丛状蛋白D1的细胞内结构域释放RhoJ，RhoJ通过与Cdc42竞争其共同的效应蛋白来诱导肌动蛋白解聚。RhoJ进一步介导Sema3E诱导的丛状蛋白D1与血管内皮生长因子受体（VEGFR）2的结合以及p38的激活。在用VEGF-A刺激后，RhoJ促进包含VEGFR2、丛状蛋白D1和神经纤毛蛋白-1的全受体复合物的形成，从而防止VEGFR2降解并维持细胞内信号转导。RhoJ的这些多效性作用是视网膜血管生成中EC定向迁移所必需的。本综述强调了血管生物学领域中关于Rho GTP酶的最新见解，因为考虑它们作为治疗视网膜血管疾病中异常血管生成和高通透性靶点的潜力将是有益的。
