Endothelial response to glucose: dysfunction, metabolism, and transport

Abstract

The endothelial cell response to glucose plays an important role in both health and disease. Endothelial glucose-induced dysfunction was first studied in diabetic animal models and in cells cultured in hyperglycemia. Four classical dysfunction pathways were identified, which were later shown to result from the common mechanism of mitochondrial superoxide overproduction. More recently, non-coding RNA, extracellular vesicles, and sodium-glucose cotransporter-2 inhibitors were shown to affect glucose-induced endothelial dysfunction. Endothelial cells also metabolize glucose for their own energetic needs. Research over the past decade highlighted how manipulation of endothelial glycolysis can be used to control angiogenesis and microvascular permeability in diseases such as cancer. Finally, endothelial cells transport glucose to the cells of the blood vessel wall and to the parenchymal tissue. Increasing evidence from the blood-brain barrier and peripheral vasculature suggests that endothelial cells regulate glucose transport through glucose transporters that move glucose from the apical to the basolateral side of the cell. Future studies of endothelial glucose response should begin to integrate dysfunction, metabolism and transport into experimental and computational approaches that also consider endothelial heterogeneity, metabolic diversity, and parenchymal tissue interactions.

Keywords: SGLT2; blood brain barrier; diabetes; extracellular vesicles; glucose transport; glycolysis.

Figure 1.. Endothelial cells become dysfunctional in high glucose environments, which is connected to glucose metabolism and transport.

In normal glucose, endothelial cells take up glucose from the blood via glucose transporters (GLUT) and sodium-glucose cotransporters (SGLT). Glucose can then be metabolized, primarily via glycolysis. Pyruvate is shuttled into the mitochondria to be metabolized in the tricarboxylic acid (TCA) cycle or converted to lactate and transported out of the cell via monocarboxylate transporters (MCT). Alternatively, glucose can be transported to the vessel wall or parenchymal tissue paracellularly through cell–cell junctions or transcellularly via GLUTs and SGLTs at the cell abluminal surface. In high glucose, endothelial cells take up more glucose and increase glucose metabolism via glycolysis. Some of the excess glycolytic intermediate metabolites are shunted down glycolytic side branch pathways that contribute to endothelial dysfunction, including the polyol, pentose phosphate, hexosamine biosynthetic, and methylglyoxal pathways. Side branch pathway metabolism is further increased by superoxide overproduction from excess mitochondrial metabolism. Excess glucose also increases protein kinase C (PKC) activation, changes microRNA (miRNA) and long non-coding RNA (lncRNA) expression, and increases extracellular vesicle (EV) release while changing EV contents.