Hyperglycemia‐induced Glycosylation: A Driving Force for Vascular Dysfunction in Diabetes?
Authors: Hoffmann Brian R. , Widlansky Michael E. , Greene Andrew S. 
Published: November 2023

Vascular endothelial dysfunction leading to increased risk of coronary artery disease, peripheral vascular disease, and impaired ability to respond to tissue ischemia remains an important clinical problem in type 2 diabetic mellitus (T2DM) patients. Hyperglycemia, a major causative factor in T2DM, is among causes leading to these vascular complications, although the underlying mechanisms of dysfunction are not well understood. It is known that early intensive glycemic control reduces the risk of vascular complications during T2DM; however, there is a large gap in studies of the etiology of hyperglycemia‐induced endothelial dysfunction. T2DM patients with a high glycation index of hemoglobin A1C (HbA1c) have a greater risk of microvascular and macrovascular complications, suggesting there is a correlation between hyperglycemia‐induced glycosylation and the progression of T2DM vascular complications. Clinically, HbA1c glycosylation levels have been used as a predictor of retinopathy, nephropathy, and cardiovascular complications and lowering HbA1c glycosylation levels correlates with improved vascular phenotypes. These studies suggest that high levels of blood glucose correlate with biochemically favorable Maillard reactions that cause spontaneous glycosylation events in the vasculature. The objective of this study was to expand our knowledgebase on the influence of hyperglycemia‐induced glycosylation events in the vascular endothelium and its contribution to the onset and progression of T2DM. Initial characterization of the effects of hyperglycemia on ex vivo vasodilation and in vitro tube formation assays exhibited impaired endothelial phenotypes. In addition, enzymatic removal of glycosylations on the endothelial cell surface was able to restore normal phenotypes. In order to identify specific mechanisms behind the observed endothelial impairment a combination of glycoproteomic, phosphoproteomic, and genomic methodology was used on normal and high glucose treated rat microvascular endothelial cells. These analyses revealed differential glycosylation of important endothelial cell surface receptors, ion channels, and adhesive protein targets; including the angiotensin II (AT1) and serotonin (5HT‐2A) receptors. Additionally, further analysis of gene expression and the synergistic balance between intracellular O‐GlcNAcylation and phosphorylation of treated rat endothelial cells indicated alterations of vasoreactive pathways, inflammatory factors (IL6, IL1R1a), and VEGF signaling important for endothelial function. Overall, this study identified multiple hyperglycemia‐induced endothelial signaling alterations that potentially contribute to peripheral vascular disease in T2DM.Support or Funding InformationThis work was supported by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (K01DK105043 to BRH) and the Medical College of Wisconsin (MCW) Research Affairs Committee through a new faculty pilot grant (to BRH). Additional support was provided by the MCW Biotechnology and Bioengineering Center.