Hyperglycemia‐driven glycosylation of the AT1 receptor in the vascular endothelium (1086.8)

Abstract

Vascular dysfunction, leading to coronary artery and peripheral vascular disease, remains an important problem in type 2 diabetes mellitus (T2DM) patients. In T2DM, hyperglycemia is a major causative factor for vascular endothelial dysfunction, yet there is a large gap in studies of the etiology behind the underlying mechanisms. This study evaluated the hypothesis that hyperglycemia‐induced endothelial glycoproteome changes lead to alterations in homeostatic endothelial signaling pathways. To test this hypothesis, innovative advances in glycoproteome and phosphoproteome enrichment, highly sensitive mass spectrometry, and relevant functional assays were utilized to assess alterations of rat microvascular endothelial cells (RMVECs) cultured in normal (5 mM) or high glucose (25 mM). Differential glycosylation of the type‐1A angiotensin II receptor (AT1; p=0.029) on the RMVEC surface was observed during hyperglycemia, along with glycosylation on other important vascular targets. Additionally, hyperglycemia‐induced changes in the synergistic balance of intracellular O‐GlcNAcylation and phosphorylation, along with inhibition of RMVEC tube formation, revealed alterations in AT1‐receptor signaling processes. Overall, this study identified glycoproteome alterations converging to cause endothelial dysfunction and potentially peripheral vascular disease during hyperglycemia and T2DM.Grant Funding Source: Supported by HL082798 and T32 HL094273