Central Role of Metabolism in Endothelial Cell Function and Vascular Disease

Abstract

The importance of endothelial cell (EC) metabolism and its regulatory role in the angiogenic behavior of ECs during vessel formation and in the function of different EC subtypes determined by different vascular beds has been recognized only in the last few years. Even more importantly, apart from a role of nitric oxide and reactive oxygen species in EC dysfunction, deregulations of EC metabolism in disease only recently received increasing attention. Although comprehensive metabolic characterization of ECs still needs further investigation, the concept of targeting EC metabolism to treat vascular disease is emerging. In this overview, we summarize EC-specific metabolic pathways, describe the current knowledge on their deregulation in vascular diseases, and give an outlook on how vascular endothelial metabolism can serve as a target to normalize deregulated endothelium.

FIGURE 1.

Overview of endothelial metabolism Simplified scheme of the recently described metabolic pathways in endothelial cells and their known key regulators. 3PG, 3-phosphoglycerate; α-KG, alpha-ketoglutarate; acetyl-CoA, acetylcoenzyme A; ARG, arginase; ATP, adenosine triphosphate; CPT1a, carnitine palmitoyltransferase 1a; eNOS, endothelial nitric oxide synthase; FAD⁺/FADH2, flavin adenine dinucleotide; F1,6P₂, fructose-1,6-bisphosphate; F2,6P₂, fructose-2,6-bisphosphate; FA, fatty acid; F6P, fructose-6-phosphate; 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; GP, glycogen phosphorylase; GSH, glutathione; GSSG, glutathione disulphide; GYS, glycogen synthase; LDH, lactate dehydrogenase; NAD(P)⁺/NAD(P)H, nicotinamide adenine dinucleotide (phosphate); NO, nitric oxide; OAA, oxaloacetate; PFK1, phosphofructokinase-1; PFKFB3, phosphofructokinase-2/fructose-2,6-bisphosphatase isoform 3; R5P, ribose-5-phosphate; ROS, reactive oxygen species; TCA, tricarboxylic acid (cycle); TKT, transketolase; UDP-Glucose, uridine diphosphate glucose; UDP-GlcNAc, uridine diphosphate-N-acetylglucosamine.

FIGURE 2.

EC proliferation depends on FAO for nucleotide synthesis Schematic overview of the functional role of oxidation of fatty acid (FAO) in EC proliferation. ECs used FAO to synthesize nucleotides to maintain the proliferating state. Upon uptake of fatty acids by the cell, they are transported by CPT1a into the mitochondria, where FAO takes places. The end-product (acetyl-CoA) can enter the TCA cycle and contribute to nucleotide synthesis, generating ribonucleotide triphosphate (rNTPs) and deoxynucleotide triphosphates (dNTPs), or to amino acid synthesis. By inhibiting FAO in ECs via blockade of the rate-limiting enzyme CPT1a, the dNTP pool decreases, leading to reduced proliferation. CPT1a, carnitine palmitoyltransferase 1a; TCA, tricarboxylic acid (cycle).

FIGURE 3.

Implications of endothelial ROS on vascular disorders Scheme depicting intracellular sources of endothelial ROS, e.g., mediated via high glucose levels and eNOS uncoupling, which can mediate endothelial dysfunction and thereby promote different vascular diseases, including atherosclerosis, ischemic disease, aneurysm, diabetic vasculopathy, etc. (for detail see text and Table 1). GSH, gluthatione; GSSG, oxidized gluthatione; NADP⁺/NADPH, nicotinamide adenine dinucleotide phosphate; G6PD, glucose-6-phosphate dehydrogenase; DAG, diacylglycerol; PKC, protein kinase C; NO, nitric oxide; NOX, NO synthase; oxLDL, oxidized low-density lipoprotein; BH4, tetrahydrobiopterin; ADMA, asymmetric dimethyl arginine; AGEs, advanced glycation end products.

FIGURE 4.

Induction of tumor vessel normalization upon glycolysis inhibition in TECs Schematic representation of untreated tumor vasculature (left) with highly leaky vessels and poor pericyte coverage, leading to badly perfused tumor tissue and facilitated intravasation of tumor cells. Upon reduction of endothelial glycolysis via PFKFB3 blockade, the hyperproliferative and hyperglycolytic phenotype of tumor blood vessels is normalized (right), leading to smoothly aligned ECs with functional VE-cadherin junctions and matured vasculature containing tightly attached pericytes, and reduced expression by the TECs of cancer adhesion molecules. These mechanisms improve perfusion and chemotherapy delivery (not shown), and limit intravasation and subsequent metastasis. PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3.

FIGURE 5.

Metabolism of normal endothelial cells vs. tumor endothelial cells Schematic overview to highlight the differential regulation of key metabolic pathways in normal endothelial cells (NECs) vs. tumor endothelial cells (TECs). NECs (left) can produce nucleotides using the pentose phosphate pathway (PPP) and the serine biosynthesis pathway (SBP), which can be fuelled from glycolytic intermediates (respectively, G6P and 3PG); however, only a minor part is shuttled through the PPP and SBP to generate nucleotides. Serine can be converted to glycine and contribute, in addition to the one carbon metabolism (1-C), to purine synthesis. In contrast, TECs (right) are highly glycolytic and divert more glycolytic intermediates into side pathways including the PPP and SBP for nucleotide synthesis. 3PG, 3-phosphoglycerate; G6P, glucose-6-phosphate; PRPP, phosphoribosyl pyrophosphate; R5P, ribose 5-phosphate.

FIGURE 6.

Glycolysis is crucial for maintaining energy levels necessary for endocytosis of VE-cadherin Graphical summary of the underlying processes of VE-cadherin endocytosis in ECs. VE-cadherin is a component of endothelial cell-to-cell adherens junctions and has a key role in the maintenance of vascular integrity. In the tumor environment (left), the endothelial cell barrier becomes loosened in part by increased endocytosis of VE-cadherin (low membranal VE-cadherin). Endocytosis, requiring actin remodelling, is a high-energy (ATP)-demanding process. ATP generation in ECs is primarily generated during the breakdown of glucose to pyruvate (glycolysis). Inhibition of glycolysis through the blockade of PFKFB3 (right) decreases VE-cadherin endocytosis (higher membranal VE-cadherin) and thereby promotes ECs barrier tightness.