Abstract
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.
Highlights
Retinal vascular diseases are characterized by aberrant angiogenesis accompanying the dysregulated proliferation and migration of endothelial cells (ECs), which causes vitreous hemorrhages and, tractional retinal detachment [1,2]
We summarize the accumulated knowledge of Rho GTPases in the field of vascular biology, with particular emphasis on RhoJ
Once the retinal blood vessels are formed, the association of ECs with pericytes facilitates the maturation of the EC–EC junctions and the suppression of transcytosis, which leads to the establishment of the blood–retina barrier (BRB) [42,43,44]
Summary
Retinal vascular diseases are characterized by aberrant angiogenesis accompanying the dysregulated proliferation and migration of endothelial cells (ECs), which causes vitreous hemorrhages and, tractional retinal detachment [1,2]. While various cytokines have been implicated in these pathologies, vascular endothelial growth factor (VEGF) A is a major driver of both angiogenesis and vascular hyperpermeability, which has been corroborated with the therapeutic potency of anti-VEGF agents in diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity [5,6,7] In these diseases, retinal neurons, glial cells, and retinal pigment epithelium cells under hypoxia or inflammation upregulate expression levels of VEGF-A, which binds to a tyrosine kinase VEGF receptor (VEGFR) 2 on ECs [5,6,7]. Upon stimulation with VEGF-A, RhoJ facilitates the formation of a holoreceptor complex comprising VEGFR2, PlexinD1, and neuropilin-1, thereby preventing the degradation of internalized VEGFR2 and prolonging downstream signal transduction events [17] These pleiotropic functions of RhoJ promote directional EC migration in retinal angiogenesis both under physiological and pathological settings [17]. This information will provide a clue to consider their potential as targets for the treatment of retinal vascular diseases
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
