Endothelial Metabolism Driving Angiogenesis
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Abstract:
Angiogenesis has been traditionally studied by focusing on growth factors and other proangiogenic signals, but endothelial cell (EC) metabolism has not received much attention. Nonetheless, glycolysis, one of the major metabolic pathways that converts glucose to pyruvate, is required for the phenotypic switch from quiescent to angiogenic ECs. During vessel sprouting, the glycolytic activator PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3) promotes vessel branching by rendering ECs more competitive to reach the tip of the vessel sprout, whereas fatty acid oxidation selectively regulates proliferation of endothelial stalk cells. These studies show that metabolic pathways in ECs regulate vessel sprouting, more importantly than anticipated. This review discusses the recently discovered role of glycolysis and fatty acid oxidation in vessel sprouting. We also highlight how metabolites can influence EC behavior as signaling molecules by modulating posttranslational modification.Keywords:
Sprouting angiogenesis
Metabolic pathway
Fatty Acid Metabolism
Mural cell
Pericyte
Sprouting angiogenesis
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Contrary to the textbook portrayal of glycolysis as a single pathway conserved across all domains of life, not all sugar-consuming organisms use the canonical Embden–Meyerhoff–Parnass (EMP) glycolytic pathway. Prokaryotic glucose metabolism is particularly diverse, including several alternative glycolytic pathways, the most common of which is the Entner–Doudoroff (ED) pathway. The prevalence of the ED pathway is puzzling as it produces only one ATP per glucose—half as much as the EMP pathway. We argue that the diversity of prokaryotic glucose metabolism may reflect a tradeoff between a pathway’s energy (ATP) yield and the amount of enzymatic protein required to catalyze pathway flux. We introduce methods for analyzing pathways in terms of thermodynamics and kinetics and show that the ED pathway is expected to require several-fold less enzymatic protein to achieve the same glucose conversion rate as the EMP pathway. Through genomic analysis, we further show that prokaryotes use different glycolytic pathways depending on their energy supply. Specifically, energy-deprived anaerobes overwhelmingly rely upon the higher ATP yield of the EMP pathway, whereas the ED pathway is common among facultative anaerobes and even more common among aerobes. In addition to demonstrating how protein costs can explain the use of alternative metabolic strategies, this study illustrates a direct connection between an organism’s environment and the thermodynamic and biochemical properties of the metabolic pathways it employs.
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Metabolic flux analysis
Carbohydrate Metabolism
Adenosine triphosphate
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Endothelial progenitor cells are being broadly explored for the treatment of ischemic cardiovascular diseases, but their response to molecules commonly used to promote the growth of new blood vessels has not been fully characterized. In this study, angiogenic sprout formation in a 3-dimensional, in vitro model by one type of endothelial progenitor, outgrowth endothelial cells (OECs), was characterized in response to exposure to stromal cell-derived factor (SDF) and vascular endothelial growth factor (VEGF) and then compared to mature endothelial cells. Exposure to SDF alone did not increase angiogenic sprouting in comparison to control media, while a combination of VEGF and SDF demonstrated greater potency than VEGF alone for all cell types. Together, VEGF and SDF reduced the sprout initiation time and maintained sprouting levels over time. In direct competition with mature endothelial cells, OECs preferentially localized to the tip cell position, suggesting an enhanced sprouting potential. Overall, these results reveal the impact of the combination of VEGF and SDF on endothelial cell sprouting, and support the enhanced potential of OECs, as opposed to mature endothelial cells, for treating ischemic diseases.
Sprouting angiogenesis
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Abstract Cardiovascular disease (CVD) is a major threat to human health, accounting for 46% of non-communicable disease deaths. Glycolysis is a conserved and rigorous biological process that breaks down glucose into pyruvate, and its primary function is to provide the body with the energy and intermediate products needed for life activities. The non-glycolytic actions of enzymes associated with the glycolytic pathway have long been found to be associated with the development of CVD, typically exemplified by metabolic remodeling in heart failure, which is a condition in which the heart exhibits a rapid adaptive response to hypoxic and hypoxic conditions, occurring early in the course of heart failure. It is mainly characterized by a decrease in oxidative phosphorylation and a rise in the glycolytic pathway, and the rise in glycolysis is considered a hallmark of metabolic remodeling. In addition to this, the glycolytic metabolic pathway is the main source of energy for cardiomyocytes during ischemia–reperfusion. Not only that, the auxiliary pathways of glycolysis, such as the polyol pathway, hexosamine pathway, and pentose phosphate pathway, are also closely related to CVD. Therefore, targeting glycolysis is very attractive for therapeutic intervention in CVD. However, the relationship between glycolytic pathway and CVD is very complex, and some preclinical studies have confirmed that targeting glycolysis does have a certain degree of efficacy, but its specific role in the development of CVD has yet to be explored. This article aims to summarize the current knowledge regarding the glycolytic pathway and its key enzymes (including hexokinase (HK), phosphoglucose isomerase (PGI), phosphofructokinase-1 (PFK1), aldolase (Aldolase), phosphoglycerate metatase (PGAM), enolase (ENO) pyruvate kinase (PKM) lactate dehydrogenase (LDH)) for their role in cardiovascular diseases (e.g., heart failure, myocardial infarction, atherosclerosis) and possible emerging therapeutic targets.
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Phosphoglycerate mutase
Glucose-6-phosphate isomerase
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As a classic prescription, Huangqin Tang (HQT) has been widely applied to treat ulcerative colitis (UC), although its pharmacological mechanisms are not clear. In this study, urine metabolomics was first analysed to explore the therapeutic mechanisms of HQT in UC rats induced by TNBS. We identified 28 potential biomarkers affected by HQT that might cause changes in urine metabolism in UC rats, mapped the network of metabolic pathways, and revealed how HQT affects metabolism of UC rats. The results showed that UC affects amino acid metabolism and biosynthesis of unsaturated fatty acids and impairs the tricarboxylic acid cycle (TCA cycle). UC induced inflammatory and gastrointestinal reactions by inhibiting the transport of fatty acids and disrupting amino acid metabolism. HQT plays key roles via regulating the level of biomarkers in the metabolism of amino acids, lipids, and so on, normalizing metabolic disorders. In addition, histopathology and other bioinformatics analysis further confirm that HQT altered UC rat physiology and pathology, ultimately affecting metabolic function of UC rats.
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Hyperuricemia (HUA) as a metabolic disease is closely associated with metabolic disorders. The etiology and pathogenesis of HUA are not fully understood, so there is no radical cure so far. Metabolomics, a specialized study of endogenous small molecule substances, has become a powerful tool for metabolic pathway analysis of selected differential metabolites, which is helpful for initially revealing possible development mechanisms of various human diseases. Twenty HUA patients and 20 healthy individuals participated in the experiment, and ultrahigh performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS) was employed to investigate serum samples to find differential metabolites. The statistical techniques used were principal component analysis and orthogonal partial least-squares discriminant analysis. The differences in metabolomics results of samples after pretreatment with different solvents were compared, 38, 20, 26, 28, 33, 50, and 40 potential differential metabolites were found, respectively, in HUA patient samples, and each group involved different metabolic pathways. Repetitive metabolites were removed, 138 differential metabolites in HUA serum were integrated for analysis, and the human body was affected by 7 metabolic pathways of glycerophospholipid metabolism, sphingolipid metabolism, arachidonic acid metabolism, linoleic acid metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and α-linolenic acid metabolism. In this work, the metabolomics approach based on UPLC-Q-TOF/MS was employed to investigate serum metabolic changes in HUA patients, 138 potential differential metabolites related to HUA were identified, which provided associations of lipids, amino acids, fatty acids, organic acids, and nucleosides profiles of HUA individuals. Metabolic pathways involved in glycerophospholipid metabolism, sphingolipid metabolism, arachidonic acid metabolism, linoleic acid metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and a-linolenic acid metabolism shed light on the understanding of the etiology and pathogenesis process of HUA.
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To illustrate the metabolic regulatory mechanisms of Jiangzhi decoction (JZD) against non-alcoholic fatty liver disease (NAFLD).High-fat diet (HFD)-induced NAFLD rats were treated with JZD. The pathological morphology, lipid indexes and liver function were detected. Metabolic profiles were examined by liquid chromatography-mass spectrometry (LC-MS). Multivariate and univariate statistical analysis were used to search the differential metabolites. Pathway enrichment analysis was carried out using Kyoto Encyclopedia of Genes and Genomes database. Compound-gene networks were built by Cytoscape software.JZD significantly alleviated the pathological conditions and improved lipid index levels. Multivariate analysis showed a good separation among different groups. Three hundred and twenty-seven metabolites in HFD versus control and 301 metabolites in JZD versus HFD were identified to be significantly different. Pathway enrichment analysis showed that lipid metabolism pathways were prominent altered pathways. Importantly, the relationships were more distant between JZD and HFD groups in all five lipid metabolism pathways, including arachidonic acid metabolism, linoleic acid metabolism, biosynthesis of unsaturated fatty acids, glycerophospholipid metabolism and sphingolipid metabolism, while those were obviously closer between JZD and control groups. Simultaneously, JZD treatment restored the levels of disturbed differential metabolites in HFD group.JZD had an effect on alleviating NAFLD via regulating relevant lipid metabolism.
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Fatty Acid Metabolism
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Decoction
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