The glycolytic process in endothelial cells and its implications

Abstract

Endothelial cells play an obligatory role in regulating local vascular tone and maintaining homeostasis in vascular biology. Cell metabolism, converting food to energy in organisms, is the primary self-sustaining mechanism for cell proliferation and reproduction, structure maintenance, and fight-or-flight responses to stimuli. Four major metabolic processes take place in the energy-producing process, including glycolysis, oxidative phosphorylation, glutamine metabolism, and fatty acid oxidation. Among them, glycolysis is the primary energy-producing mechanism in endothelial cells. The present review focused on glycolysis in endothelial cells under both physiological and pathological conditions. Since the switches among metabolic processes precede the functional changes and disease developments, some prophylactic and/or therapeutic strategies concerning the role of glycolysis in cardiovascular disease are discussed.

Keywords: cardiovascular disease; endothelial cells; glucose transporters; glycolysis; hexokinase 2; phosphofructokinase/fructose bisphosphatase 3; pyruvate kinase enzyme M2.

Fig. 1. Interaction of glycolysis, oxidative phosphorylation, glutaminolysis, and fatty acid oxidation.

More than ten enzymes participate in the glycolysis process, transferring glucose to lactate and producing ATP molecules, including the glucose transporters (GLUT1 and GLLUT4), HK2, PFK, and PKM2. Products from the pyruvate kinase go either into the TCA cycle under aerobic conditions or to lactic acid under anaerobic conditions. PFKFB3 is an allosteric activator of PFK and plays a crucial role in regulating the glycolytic process. MPC transports pyruvate in the cytosol across the inner mitochondrial membrane. HK2 protein locates at the outer mitochondrial membrane. Increased mitochondrial fission separates HK2 molecules from mitochondria, resulting in mitochondrial permeability transition pore opening and increased oxidative stress. Glutamine metabolism deaminates glutamine to glutamate by GLS1, serves as a critical process in replenishing the carbon intermediates for maintaining the mitochondrial TCA cycle. PKM2 protein is part of the eNOS complex, and eNOS has intrinsic inhibitory effects on PKM2 activity through nitrosation under control conditions.

Fig. 2. The blood–brain barrier (BBB), consisted of endothelial cells and pericytes, plays a crucial role in protecting the central nervous system from peripheral inflammatory and toxic materials.

GLUTs, coupled with HK2 protein in the abluminal side, facilitate the influx of glucose from the blood into the brain. Both BBB endothelial cells and pericytes transfer mitochondria and glucose to astrocytes, providing energy to poor-energic astrocytes under pathophysiological conditions. When the glycolysis is compromised under pathological conditions, endothelial cells switch to other metabolic processes, mainly oxidative phosphorylation, for energy-sustaining, resulting in increased oxidative stress and enhanced inflammation. The latter breaks tight junction and increases the BBB permeability. The presence of occludin in pericytes, also acting as an NADH oxidase and a regulator of AMPK, in the BBB pericyte is depleted under inflammatory conditions, resulting in reduced AMPK signaling and glycolysis process.