Endothelial cell metabolism in normal and diseased vasculature

Abstract

Higher organisms rely on a closed cardiovascular circulatory system with blood vessels supplying vital nutrients and oxygen to distant tissues. Not surprisingly, vascular pathologies rank among the most life-threatening diseases. At the crux of most of these vascular pathologies are (dysfunctional) endothelial cells (ECs), the cells lining the blood vessel lumen. ECs display the remarkable capability to switch rapidly from a quiescent state to a highly migratory and proliferative state during vessel sprouting. This angiogenic switch has long been considered to be dictated by angiogenic growth factors (eg, vascular endothelial growth factor) and other signals (eg, Notch) alone, but recent findings show that it is also driven by a metabolic switch in ECs. Furthermore, these changes in metabolism may even override signals inducing vessel sprouting. Here, we review how EC metabolism differs between the normal and dysfunctional/diseased vasculature and how it relates to or affects the metabolism of other cell types contributing to the pathology. We focus on the biology of ECs in tumor blood vessel and diabetic ECs in atherosclerosis as examples of the role of endothelial metabolism in key pathological processes. Finally, current as well as unexplored EC metabolism-centric therapeutic avenues are discussed.

Keywords: angiogenesis; atherosclerosis; cancer; diabetes mellitus; endothelial metabolism.

Figure 1. General metabolism in healthy ECs

Schematic and simplified overview of general EC metabolism. Abbreviations used: 3PG: 3-phosphogylcerate; α-KG: α-ketoglutarate; ATP: adenosine triphosphate; DHAP: dihydroxyacetone phosphate; ETC: electron transport chain; Fu1,6P₂: fructose-1,6-bisphosphate; F2,6P₂: fructose-2,6-bisphosphate; F6P: fructose-6-phosphate; FA: fatty acid; G3P: glyceraldehyde-3-phosphate; G6P: glucose-6-phosphate; GLS: glutaminase; GlucN6P: glucosamine-6-phosphate; hCYS: homocysteine; mTHF: 5-methyltetrahydrofolate; NADPH: nicotinamide adenine dinucleotide phosphate; NO: nitric oxide; OAA: oxaloacetate; PFK1: phosphofructokinase-1; PFKFB3: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; R5P: ribose-5-phosphate; ROS: reactive oxygen species; Ru5P: ribulose-5-phosphate; SAM: S-adenosylmethionine; SLC1A5: solute carrier family 1 member 5; THF: tetrahydrofolate; UDP-GlucNAc: uridine diphosphate N-acetylglucosamine.

Figure 2. Metabolic pathways involved in disease characterized by EC dysfunction

A, In diabetes, hyperglycemia triggers mainly increased ROS production through eNOS uncoupling and PPP impairment resulting in stalled glycolytic flux with glycolytic intermediates being diverted into alternative metabolic pathways leading to additional excess ROS and AGEs production. B, Atherosclerosis is characterized at a metabolic level mainly by eNOS uncoupling resulting in excess ROS production and loss of NO-dependent vasodilation. Abbreviations used: as in Figure 1. 1,3BPG: 1,3-bisphosphoglycerate; 3DG: 3-deoxyglucosone; ADMA: asymmetric dimethyl arginine; AGE: advanced glycation end product; AGXT2: alanine-glyoxylate aminotransferase; AR: aldose reductase; BH₂: 7,8-dihydrobiopterin; BH₄: tetrahydrobiopterin; DAG: diacylglycerol; DDAH: dimethyl-arginine dimethyl-aminohydrolase; DHFR: dihydrofolate reductase; eNOS: endothelial nitric oxide synthase; G6PDH: glucose-6-phosphate dehydrogenase; GADPH: glyceraldehyde-3-phosphate dehydrogenase; GFAT: glutamine fructose-6-phosphate amidotransferase; GGPP: geranylgeranyl pyrophosphate; GTP: guanosine triphosphate; GTPCH: GTP cyclohydrolase; HMG-CoA: hydroxymethylglutaryl coenzyme A; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; MET: methionine; MTHFR: methylenetetrahydrofolate reductase; PARP1: polyADP-ribose polymerase 1; PKC: protein kinase C; PPP: pentose phosphate pathway; SDH: sorbitol dehydrogenase.

Figure 3. Metabolic pathways in tumor vessels and metabolic interactions between cancer and stromal cells

A, ECs in tumor vasculature are presumably characterized by increased glycolysis. B, Metabolic interactions between cancer and stromal cells. Abbreviations used: as in Figures 1 and 2. ER: endoplasmic reticulum; GLUT: glucose transporter; HIF: hypoxia-inducible factor; IL-8: interleukin-8; LDH: lactate dehydrogenase; PHD: prolyl hydroxylase domain.