Understanding The Role of Protein O-GlcNAcylation (O-GlcNAc) in Aldosterone-induced Vascular Dysfunction

O-GlcNAc (O-glycosylation with N-acetylglucosamine) is a post-translational modification that regulates intracellular processes by changing protein function and subcellular localization. O-GlcNAc is mainly controlled by two key enzymes OGT (O-GlcNAc transferase) and OGA (O-GlcNAcase). We previously demonstrated that aldosterone, a mineralocorticoid hormone, induces vascular protein O-GlcNAcylation. This study aims to understand the role of O-GlcNAc on aldosterone-induced vascular dysfunction. To do so, we generated two different conditional OGT knockout (KO) mouse models in endothelial cells (ecOGT) and vascular smooth muscle cells (smOGT). They were submitted to aldosterone infusion (600 g/kg/day) for 14 days with osmotic mini-pumps. Additionally, human endothelial cells (EA.hy926) and iPSC-derived vascular smooth muscle cells (VSMC) were cultured and treated with aldosterone to determine changes in O-GlcNAc levels and OGT and OGA expression. The aortas of wild-type mice treated with aldosterone displayed increased O-GlcNAc levels and vascular dysfunction. ecOGT KO mice infused with aldosterone did not exhibit vascular dysfunction. On the other hand, smOGT mice showed impaired vascular reactivity, independently of aldosterone infusion, indicating a physiological role for O-GlcNAc in vascular contraction. in vitro, EA.hy926 cells treated with aldosterone at different times exhibited increased protein O-GlcNAcylation and no differences were found in OGT or OGA protein content. Similar results were observed in VSMC treated with aldosterone. These data indicate that vascular protein O-GlcNAcylation in response to aldosterone stimulation plays different roles within the vascular wall and may represent a novel mechanism by which aldosterone induces vascular dysfunction. Ongoing experiments involve proteomics studies in VSMC to identify key targets that could be O-GlcNAcylated in response to aldosterone and influence vascular tone control. This study is funded by FAPESP (The São Paulo Research Foundation, Brazil, Process numbers: 2021/09273-6 and 2023/10877-9) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.