Robo4, also known as Roundabout4, is an endothelial-specific transmembrane receptor belonging to the Roundabout (Robo) family of axon guidance molecules. It participates in endothelial cell migration, proliferation, and angiogenesis, and is crucial for maintaining vasculature homeostasis. It is involved in pathways such as those mediated by Slit ligands, and interacts with proteins like UNC5B, IQGAP1, and TRAF7. Genetic models, especially KO/CKO mouse models, are valuable for studying its functions [1,2,3].

In KO mouse models, Robo4-deficiency exacerbates PTGS2-associated inflammatory diseases, including arthritis, edema, and pain, revealing its role in suppressing the inflammatory response and vascular hyperpermeability [2]. Endotoxemia models using Robo4 -/- mice show increased mortality and vascular leakage, indicating that Robo4-TRAF7 complex is a negative regulator of inflammatory hyperpermeability [5]. In the context of radiation-induced injury, Robo4 deletion in endothelial cells leads to increased permeability, while overexpression mitigates irradiation-induced damage to endothelial junctions [6]. In the case of diabetic retinopathy, inhibition of TET2-mediated ROBO4 hypomethylation can ameliorate the dysfunction of human retinal endothelial cells and retinal vascular abnormalities [4].

In conclusion, Robo4 plays essential roles in maintaining vascular integrity, suppressing inflammation, and protecting against radiation-induced endothelial damage. Studies using KO/CKO mouse models have provided insights into its functions in diseases such as inflammatory diseases, radiation-related injuries, and diabetic retinopathy, highlighting its potential as a therapeutic target.