Endothelial Sestrin2 Coordinates Multiple Protective Pathways to Maintain Angiogenic Function in Diabetes-Associated Endothelial Dysfunction

Diabetes mellitus is prevalent worldwide, with vascular complications responsible for over 70% of deaths associated with the condition. Methylglyoxal (MGO), a reactive α-dicarbonyl molecule generated as a by-product of glycolysis, is a significant modulator of vascular dysfunction in diabetes. Sestrin2 (SESN2), a protein induced by stress, has been recognized as a vital regulator of cellular homeostasis and stress responses. Although SESN2's role in cellular defense is gaining recognition, its precise function in endothelial cells under diabetes conditions remains poorly understood. This study examines the role of SESN2 in preserving endothelial cell function and angiogenic capacity in diabetic environments, particularly under MGO-induced stress. The study reveals that SESN2 is a vital regulator of many protective pathways through both loss-of-function and gain-of-function methodologies in EA.hy926 endothelial cells. SESN2 overexpression significantly maintained tubular network formation, proliferation, and invasive capability under MGO stress, whereas SESN2 suppression exacerbated MGO-induced impairments. SESN2 was identified to orchestrate the activation of the NRF2/HO-1 antioxidant pathway while simultaneously enhancing VEGF-C expression, offering a dual strategy for cellular protection and angiogenesis enhancement. Moreover, SESN2 facilitated a regulated equilibrium of the AKT/mTOR signaling pathway, ensuring synchronized activation during stress conditions. SESN2 also regulated stress-activated MAPK pathways, diminishing P38 and ERK1/2 activation upon MGO exposure. Furthermore, SESN2 exhibited anti-apoptotic properties by positively modifying the BAX/BCL2 ratio and diminishing CASPASE3 cleavage during MGO-induced stress. These findings establish SESN2 as a pivotal regulator of endothelial cell homeostasis and angiogenic activity under diabetes conditions. This study highlights the complex protective functions of SESN2, indicating its potential as a therapeutic target for addressing diabetic vascular complications and improving patient outcomes. This work was made possible by the Qatar National Research Fund [grant No. NPRP14S-0406-210150]. The statements made herein are solely the responsibility of the authors. 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.