Angiogenesis revisited from a metabolic perspective: role and therapeutic implications of endothelial cell metabolism

Abstract

Endothelial cell (EC) metabolism has lately emerged as a novel and promising therapeutic target to block vascular dysregulation associated with diseases like cancer and blinding eye disease. Glycolysis, fatty acid oxidation (FAO) and, more recently, glutamine/asparagine metabolism emerged as key regulators of EC metabolism, able to impact angiogenesis in health and disease. ECs are highly glycolytic as they require ATP and biomass for vessel sprouting. Notably, a regulator of the glycolytic pathway, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, controls vessel sprouting during the angiogenic switch and its inhibition in tumour ECs leads to vessel normalization, thereby reducing metastasis and ameliorating chemotherapy. Moreover, FAO promotes EC proliferation through DNA synthesis, and plays an essential role in lymphangiogenesis via epigenetic regulation of histone acetylation. Pathological angiogenesis was decreased upon blockade of carnitine palmitoyltransferase 1, a regulator of FAO in ECs. More recently, metabolism of glutamine, in conjunction with asparagine, was reported to maintain EC sprouting through TCA anaplerosis, redox homeostasis, mTOR activation and endoplasmic stress control. Inactivation or blockade of glutaminase 1, which hydrolyses glutamine into ammonia and glutamate, impairs angiogenesis in health and disease, while silencing of asparagine synthetase reduces vessel sprouting in vitro In this review, we summarize recent insights into EC metabolism and discuss therapeutic implications of targeting EC metabolism.

Keywords: ASNS; CPT1a; GLS1; PFKFB3; angiogenesis; endothelial cell metabolism.

Figure 1.

PFKFB3-driven glycolysis and the central role of FAO via CPT1a function in ECs (a) Schematic of PFKFB3 as a key regulator of the glycolytic activity in ECs and the angiogenic switch. F2,6P₂, produced from F6P by PFKFB3, allosterically activates PFK1 in order to further increase glycolytic flux and quickly generate high amounts of ATP necessary for ECs to sprout. (b) Illustration of FAO metabolic pathway through the rate-controlling enzyme CPT1a in vessel sprouting. FAO and CPT1a are necessary during vessel sprout elongation to replenish the TCA cycle and to produce aspartate as a precursor of dNTPs for cell replication. (c) FAO and CPT1a are pivotal for lymphangiogenesis by promoting DNA synthesis, and thus proliferation, but also for venous-to-lymphatic EC differentiation through histone acetylation and epigenetic mechanisms.

Figure 2.

FOXO1 regulates vascular homeostasis. FOXO1 is a transcription factor ensuring EC quiescence and vascular homeostasis via c-Myc regulation. FOXO1 deletion in ECs causes severe vascular defect mediated by dysregulated EC metabolism controlled by c-Myc.

Figure 3.

Glutamine and asparagine in angiogenesis. Glutamine plays a key role in EC metabolism: it constitutes a major precursor for macromolecules biosynthesis and the main substrate for TCA cycle anaplerosis, it participates in redox homeostasis and is also shown to be a precursor for lipid biosynthesis in ECs through reductive carboxylation. Glutamine deprivation or GLS1 blockade/deletion leads to a severe defect in proliferation and migration in ECs. Asparagine supplementation (together with α-ketoglutarate) rescues the phenotype showing an interlink between glutamine catabolism pathway and asparagine synthesis via ASNS. Proliferative defect following glutamine deprivation or GLS1 blockade/deletion in ECs can be partially rescued through macropinocytosis.