Endothelial Cell Glucose Metabolism and Angiogenesis

Abstract

Angiogenesis, a process of new blood vessel formation from the pre-existing vascular bed, is a critical event in various physiological and pathological settings. Over the last few years, the role of endothelial cell (EC) metabolism in angiogenesis has received considerable attention. Accumulating studies suggest that ECs rely on aerobic glycolysis, rather than the oxidative phosphorylation pathway, to produce ATP during angiogenesis. To date, numerous critical regulators of glucose metabolism, fatty acid oxidation, and glutamine metabolism have been identified to modulate the EC angiogenic switch and pathological angiogenesis. The unique glycolytic feature of ECs is critical for cell proliferation, migration, and responses to environmental changes. In this review, we provide an overview of recent EC glucose metabolism studies, particularly glycolysis, in quiescent and angiogenic ECs. We also summarize and discuss potential therapeutic strategies that take advantage of EC metabolism. The elucidation of metabolic regulation and the precise underlying mechanisms could facilitate drug development targeting EC metabolism to treat angiogenesis-related diseases.

Keywords: angiogenesis; endothelial cell; glycolysis; metabolism; pathological angiogenesis; tumor microenvironment.

Figure 1

Differential metabolic features in three major endothelial cell (EC) populations. According to the phenotypes of ECs, they can be classified into tip cells, stalk cells, and quiescent cells during angiogenesis. Tip cells grow from the pre-existing vascular bed and are highly responsive to microenvironmental signals for migration. Stalk cells are highly proliferative and follow the tip cells to form a vessel lumen. Quiescent cells maintain vascular homeostasis. Angiogenic ECs show upregulated glycolysis gene signatures during the angiogenic switch to meet their metabolic demands. Quiescent ECs lower their glycolytic flux (35–40%) and use fatty acid oxidation (FAO) flux to maintain energy homeostasis. OXPHOS: oxidative phosphorylation.

Figure 2

Endothelial cell (EC) glycolytic flux in ocular angiogenesis and peripheral artery disease (PAD). Retinal ECs utilize both glycolysis and fatty acid oxidation (FAO) for adenosine triphosphate (ATP) production. High glucose level leads to overproduction of mitochondrial reactive oxygen species (ROS) in ECs. The accumulated glycolytic intermediates result in lower glycolytic flux, which further increases ROS in both mitochondria and cytosol in diabetic ECs. ECs in PAD show impaired oxidative phosphorylation. Under energy deficiency conditions, phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), glycolytic flux, and autophagy have protective effects on ECs in PAD. Red color represents the metabolic genes that positively regulate angiogenesis. GLUT1, glucose transporter 1; AR, aldose reductase; SDH, Sorbitol dehydrogenase; NADPH, nicotinamide adenine dinucleotide phosphate; NADH, nicotinamide adenine dinucleotide; AMPK, AMP-activated protein kinase; G3P, glyceraldehyde 3-phosphate; DHAP, dihydroxyacetone phosphate; DAG, diacylglycerol; PKC, protein kinase C; 3PG, 3-phosphoglyceric acid; FAS, fatty acid synthase; CPT1A, carnitine palmitoyltransferase 1A; GLS1, glutaminase 1; mTORC1, mammalian target of rapamycin complex 1; OXPHOS, oxidative phosphorylation; acetyl-CoA, acetyl coenzyme A; TCA, tricarboxylic acid cycle; F2,6P₂, fructose 2,6-bisphosphate; TFEB, transcription factor EB; HIF-1α, hypoxia-inducible factor 1-alpha; HRE, hypoxia response elements; Plog, mitochondrial DNA polymerase gamma; mtDNA, mitochondrial DNA.

Figure 3

Tumor endothelial cells (TECs) exhibit distinct metabolic transcriptome signatures, which are linked to their angiogenic potential. Compared with quiescent ECs, TECs utilize both glycolysis and OXPHOS for energy production. TECs (tip, stalk, and immature ECs) show upregulated glycolytic genes, including glucose transporter 1 (GLUT1), glucose transporter 3 (GLUT3), hexokinase 1 (HK1), hexokinase 2 (HK2), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), phosphofructokinase 1 (PFK1), aldolase A (ALDOA), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), pyruvate kinase M2 (PKM2), enolase 1 (ENO1), lactate dehydrogenase A (LDHA). TECs can proliferate in a lactate-rich environment. Under hypoxia, hypoxia-inducible factor-1 alpha (HIF-1α) increases the expression of GLUT1 and GLUT3 in TECs. Autophagy is increased to promote TECs to survive and adapt to metabolic needs. The star symbol indicates the steps where chemical compounds are available and the antiangiogenic effects have been tested in preclinical or clinical settings. Red color represents the upregulated metabolic genes. FA, fatty acid; MCT1/4, monocarboxylate transporter 1/4; PGK, phosphoglycerate kinase; GPI, glucose-6-phosphate isomerase.

Figure 4

EC glucose and glycogen metabolism in hypoxia and nutrient-deprivation conditions. Under hypoxia and nutrient-deprivation conditions, cellular energy levels are decreased and autophagy is upregulated by the AMPK–mTORC1 pathway. The autophagy–lysosomal pathway promotes the recycling of nutrients, including glucose, for cell survival. In response to environmental changes, ECs use glycogen as a backup energy source. Upon nutrient deprivation, TFEB translocates to the cell nucleus, where it activates target genes involved in lysosomal function and autophagy. Upregulated autophagy/lysosomal activity supports ECs to resist the detrimental effects of hypoxia and nutrient deprivation. Red color represents the key metabolic genes.