Inflammatory activation of endothelial cells increases glycolysis and oxygen consumption despite inhibiting cell proliferation

Abstract

Endothelial cell function and metabolism are closely linked to differential use of energy substrate sources and combustion. While endothelial cell migration is promoted by 2‐phosphofructokinase‐6/fructose‐2,6‐bisphosphatase (PFKFB3)‐driven glycolysis, proliferation also depends on fatty acid oxidation for dNTP synthesis. We show that inflammatory activation of human umbilical vein endothelial cells (HUVECs) by interleukin‐1β (IL‐1β), despite inhibiting proliferation, promotes a shift toward more metabolically active phenotype. This was reflected in increased cellular glucose uptake and consumption, which was preceded by an increase in PFKFB3 mRNA and protein expression. However, despite a modest increase in extracellular acidification rates, the increase in glycolysis did not correlate with extracellular lactate accumulation. Accordingly, IL‐1β stimulation also increased oxygen consumption rate, but without a concomitant rise in fatty acid oxidation. Together, this suggests that the IL‐1β‐stimulated energy shift is driven by shunting of glucose‐derived pyruvate into mitochondria to maintain elevated oxygen consumption in HUVECs. We also revealed a marked donor‐dependent variation in the amplitude of the metabolic response to IL‐1β and postulate that the donor‐specific response should be taken into account when considering targeting dysregulated endothelial cell metabolism.

Metabolic Response in Endothelial Cells to Catecholamine Stimulation Associated with Increased Vascular Permeability

“…Upon treatment, HUVECs increased respiration and became more glycolytic, which reflects a higher cellular energy demand, as these two major metabolic pathways govern ATP production. A partially similar pattern was recently observed in HUVECs upon inflammatory activation [ 52 ]. IL-1β-stimulated cells increased their oxygen and glucose consumption upon treatment.…”

Targeting glycolysis in Th2 cells by pterostilbene attenuates clinical severities in an asthmatic mouse model and IL‐4 production in peripheral blood from asthmatic patients

“…Orchestration of cellular metabolism by shifting bioenergetic preference from glycolysis to oxidative phosphorylation inhibits subsequent T cell activation and proliferation in Th2 cells [41]. During initial T cell activation, glycolysis dominates the metabolic pathway [42], resulting in extracellular glucose intake and pyruvate and acetyl-mTOR complex regulates glucose metabolism by monitoring nutrient availability and integrating signals from cytokine receptors and growth factors. Increased glycolysis in effector T cells requires activation of mTOR and increased expression of Glut1, which is a process that is mediated through the phosphatidylinositol 3-kinase (PI3K) pathway and is essential for CD4 + T cells [45].…”

“…Orchestration of cellular metabolism by shifting bioenergetic preference from glycolysis to oxidative phosphorylation inhibits subsequent T cell activation and proliferation in Th2 cells [41]. During initial T cell activation, glycolysis dominates the metabolic pathway [42], resulting in extracellular glucose intake and pyruvate and acetyl‐CoA accumulation for the TCA cycle [43,44]. The mTOR complex regulates glucose metabolism by monitoring nutrient availability and integrating signals from cytokine receptors and growth factors.…”

Parathyroid Hormone Induces Human Valvular Endothelial Cells Dysfunction That Impacts the Osteogenic Phenotype of Valvular Interstitial Cells

“…While cancer cells use glycolysis, since they are often exposed to a hypoxic environment, EC mainly relies on anaerobic glycolytic metabolism for energy production, despite their direct exposure to high levels of oxygen in the blood, which would allow them to metabolize glucose via the oxidative pathway. Although quiescent EC display a high glycolytic rate, it is lower than in proliferating EC [ 37 ] or that in inflammatory activation of EC [ 38 ]. Whereas for EC using glycolysis might be a strategy to protect themselves against oxidative stress arising from oxidative metabolism and also to transfer the maximal amounts of oxygen to perivascular cells, cancer cells prefer to use aerobic glycolysis for different reasons, including that intermediates from glycolysis can be used to synthesize macromolecules, such as nucleic acids, lipids and proteins, which are required for cancer growth and proliferation [ 39 ].…”