[Study on the Role of RASGRP2 in Vascular Endothelial Cells]

Rat sarcoma virus (RAS) guanyl nucleotide-releasing protein 2 (RASGRP2) is recognized to activate only RAS-related protein (RAP) in blood cell lineages. Previously, we identified Xenopus rasgrp2 (xrasgrp2), which is upregulated during angiogenesis, and serves as a novel angiogenesis-related gene in undifferentiated cells from Xenopus embryos. Additionally, we revealed the expression of RASGRP2 in human vascular endothelial cells (VECs); however, its role remains unclear. In this study, we aimed to investigate the involvement of RASGRP2 in apoptosis and vascular permeability of VECs, which play crucial roles in angiogenesis and disease progression. We established a vascular endothelial cell line stably overexpressing RASGRP2 to mimic its increased expression during angiogenesis and to analyze RASGRP2 signaling in detail. We found that RASGRP2 activates not only RAP1 but also RAS-related (R-RAS) and R-RAS2. Furthermore, we clarified the anti-apoptotic mechanism by which RASGRP2 inhibits the production of reactive oxygen species by nicotinamide adenine dinucleotide phosphate oxidase via RAP1 signaling, and the translocation of activated B-cell lymphoma 2-associated X protein to the mitochondria by R-RAS signaling. In addition, RASGRP2 suppresses vascular permeability by protecting against vascular endothelial-cadherin disturbance through the activation of RAP1 and R-RAS signals. These findings suggest that RASGRP2 activates both RAP1 and R-RAS in human VECs and induces multiple signal transduction pathways, thereby inhibiting apoptosis and vascular hyperpermeability. Therefore, RASGRP2 in VECs may function as a protective factor to maintain healthy blood vessels. However, further analysis is warranted to explore its potential as a therapeutic target for vascular disorders.