Metabolic reprogramming and interventions in angiogenesis

Abstract

Background: Endothelial cell (EC) metabolism plays a crucial role in the process of angiogenesis. Intrinsic metabolic events such as glycolysis, fatty acid oxidation, and glutamine metabolism, support secure vascular migration and proliferation, energy and biomass production, as well as redox homeostasis maintenance during vessel formation. Nevertheless, perturbation of EC metabolism instigates vascular dysregulation-associated diseases, especially cancer.

Aim of review: In this review, we aim to discuss the metabolic regulation of angiogenesis by EC metabolites and metabolic enzymes, as well as prospect the possible therapeutic opportunities and strategies targeting EC metabolism.

Key scientific concepts of review: In this work, we discuss various aspects of EC metabolism considering normal and diseased vasculature. Of relevance, we highlight that the implications of EC metabolism-targeted intervention (chiefly by metabolic enzymes or metabolites) could be harnessed in orchestrating a spectrum of pathological angiogenesis-associated diseases.

Keywords: Angiogenesis; Anti-tumor immunity; Cellular metabolism; Endothelial cell; Inflammation.

Graphical abstract

Fig. 1

Differential metabolic features in three major 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 signatures to meet their metabolic demands and use FAO to sustain the dNTP synthesis requirement during the angiogenesis. Quiescent ECs lower their glycolytic flux and use FAO flux to maintain energy homeostasis, as well as lower OXPHOS to limit ROS production. FAO, fatty acid oxidation; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species.

Fig. 2

Key metabolism pathways in ECs. Schematic representation of the metabolic pathways in ECs. The dashed arrow indicates allosteric activation. Individual pathways and names are highlighted by specific colors, and enzymes are denoted by red fonts. Abbreviations: 3PG, 3-phosphoglycerate; α-KG, α-ketoglutarate; acetyl-CoA, acetylcoenzyme A; ARG, arginase; ATP, adenosine triphosphate; ASNS, asparagine synthetase; CPT1α, carnitine palmitoyltransferase 1α; eNOS, endothelial nitric oxide synthase; F1,6P₂, fructose 1, 6-biphosphate; F2,6P₂, fructose 2, 6-biphosphate; F6P, fructose-6-phosphate; FA, fatty acid; FAD⁺, flavin adenine dinucleotide; FASN, fatty acid synthase; FATP, fatty acid transport protein; G1P, glucose-1-phosphate; G3P, glyceraldehyde-3-phosphate; G6P, glucose-6-phosphate; G6PD, glucose-6-phosphate dehydrogenase; GFAT, glutamine fructose-6-phosphate aminotransferase; GlcN6P, glucosamine-6-phosphate; GLS, glutaminase; GLUT1, glucose transporter 1; GP, glycogen phosphorylase; HK2, hexokinase 2; LDH, lactate dehydrogenase; NADP⁺, oxidized nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; OXPHOS, oxidative phosphorylation; PFK1, phosphofructokinase 1; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; R5P, ribose-5-phosphate; TCA, tricarboxylic acid; TKT, transketolase; UDP-GlcNAc, uridine diphosphate-N-acetylglucosamine.

Fig. 3

Metabolic interactions of ECs in the tumor microenvironment. Abbreviations used as in Fig. 1, Fig. 2. ER, endoplasmic reticulum; HIF, hypoxia inducible factor; PHD, prolyl hydroxylase domain.

Fig. 4

Regulatory mechanisms underlying metabolites and enzymes in endothelial metabolism. Distinct metabolites and enzymes play differential roles in the development of angiogenesis. The pathways and the corresponding text boxes are highlighted in different colors. Names of metabolites and metabolic enzymes are as in Fig. 1. HBP, hexosamine biosynthesis pathway; IL-8, interleukin-8; PEP, phosphoenolpyruvate; PHGDH, phosphoglycerate dehydrogenase; PKM2, pyruvate kinase isozyme M2; PPP, pentose-phosphate pathway; RhoJ, ras homolog family member J; ROS, reactive oxygen species; TECs, tumor endothelial cells.

Fig. 5

Therapeutic strategies targeting EC metabolism. Normal endothelium contains tightly adhering and interconnected ECs and an intact basement membrane supported by perivascular pericytes (left), tumor endothelium lacks this organized hierarchy and comprises structurally and functionally defective vessels with leaky ECs, disrupted basement membrane, and poor pericyte coverage, leading to perturbed blood flow and facilitating the infiltrating the infiltration of cancer cells (middle), and upon reduction of glycolysis via PFKFB3 blockade, can normalize the phenotype of tumor blood vessels (right). (Below) Normal proliferating ECs exhibit a high glycolytic flux triggered by activation of PFKFB3, and use the PPP and serine synthesis pathway (SSP) to provide R5P and serine as precursors for nucleotide and biomass synthesis (left). Tumor ECs are hyperglycolytic and show hyperactivity of the PPP and SSP to sustain the proliferative phenotype (middle). Both of them retain functional OXPHOS. Inhibiting glycolysis moderately by approximately 15%-20% (with a low dose of the PFKFB3 inhibitor 3PO) normalizes the glycolytic flux to levels observed in normal ECs, thereby decreasing the EC proliferation and re-establishing vessel barrier integrity (right). Abbreviations used as in Fig. 1, Fig. 2. 3PO, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one.