Robo4, also known as Roundabout4, is an endothelial-specific transmembrane receptor belonging to the Roundabout family of axon guidance molecules. It participates in endothelial cell migration, proliferation, and angiogenesis, and maintains vasculature homeostasis. It is involved in pathways such as those related to Slit-Robo signaling, where it can interact with ligands like Slit2 or UNC5B. Robo4 is of great biological importance as it plays a role in developmental and pathological angiogenesis, as well as in maintaining vascular integrity [1,3]. Genetic models, like gene knockout (KO) or conditional knockout (CKO) mouse models, are valuable for studying Robo4.

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 showed increased mortality and vascular leakage, indicating that the Robo4-TRAF7 complex negatively regulates inflammatory hyperpermeability [5]. In addition, in endothelial cells, Robo4 depletion promotes endothelial-to-mesenchymal transition (End-MT) through activation of both the canonical (Smad) and non-canonical (AKT/NF-κB) signaling pathways, while its overexpression alleviates irradiation-induced End-MT and protects endothelial function, which is important for hematopoietic reconstitution after radiation preconditioning [4].

In conclusion, Robo4 is crucial for maintaining vascular integrity, suppressing inflammation, and regulating endothelial-to-mesenchymal transition. KO/CKO mouse models have been instrumental in uncovering its role in inflammatory diseases and radiation-related endothelial cell damage. These findings suggest that Robo4 could be a potential therapeutic target for treating pathological angiogenesis, inflammatory diseases, and improving hematopoietic reconstitution after radiation preconditioning [1,2,4,5].

References:

1. Dai, Chang, Gong, Qiaoyun, Cheng, Yan, Su, Guanfang. 2019. Regulatory mechanisms of Robo4 and their effects on angiogenesis. In Bioscience reports, 39, . doi:10.1042/BSR20190513. https://pubmed.ncbi.nlm.nih.gov/31160487/

2. Tanaka, Masato, Shirakura, Keisuke, Takayama, Yui, Takayama, Kazuo, Okada, Yoshiaki. 2024. Endothelial ROBO4 suppresses PTGS2/COX-2 expression and inflammatory diseases. In Communications biology, 7, 599. doi:10.1038/s42003-024-06317-z. https://pubmed.ncbi.nlm.nih.gov/38762541/

3. Yadav, Suresh Singh, Narayan, Gopeshwar. 2014. Role of ROBO4 signalling in developmental and pathological angiogenesis. In BioMed research international, 2014, 683025. doi:10.1155/2014/683025. https://pubmed.ncbi.nlm.nih.gov/24689049/

4. Adzraku, Seyram Yao, Cao, Can, Zhou, Qi, Ju, Wen, Zeng, Lingyu. 2024. Endothelial Robo4 suppresses endothelial-to-mesenchymal transition induced by irradiation and improves hematopoietic reconstitution. In Cell death & disease, 15, 159. doi:10.1038/s41419-024-06546-4. https://pubmed.ncbi.nlm.nih.gov/38383474/

5. Shirakura, Keisuke, Ishiba, Ryosuke, Kashio, Taito, Aird, William C, Okada, Yoshiaki. 2019. The Robo4-TRAF7 complex suppresses endothelial hyperpermeability in inflammation. In Journal of cell science, 132, . doi:10.1242/jcs.220228. https://pubmed.ncbi.nlm.nih.gov/30510113/