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

Open Biology ◽  
2017 ◽  
Vol 7 (12) ◽  
pp. 170219 ◽  
Author(s):  
Nihed Draoui ◽  
Pauline de Zeeuw ◽  
Peter Carmeliet
Keyword(s):  
Endothelial Cell ◽  
Cell Metabolism ◽  
Redox Homeostasis ◽  
Acid Oxidation ◽  
Therapeutic Implications ◽  
Angiogenic Switch ◽  
Vessel Normalization ◽  
Promising Therapeutic Target ◽  
Health And Disease

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.

Metabolic Pathways Fueling the Endothelial Cell Drive

2019 ◽  
Vol 81 (1) ◽  
pp. 483-503 ◽  
Author(s):  
Xuri Li ◽  
Anil Kumar ◽  
Peter Carmeliet
Keyword(s):  
Endothelial Cell ◽  
Metabolic Pathways ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Redox Homeostasis ◽  
Vascular Diseases ◽  
Acid Oxidation ◽  
Therapeutic Implications ◽  
Health And Disease ◽  
Tip Cells

Endothelial cell (EC) metabolism is important for health and disease. Metabolic pathways, such as glycolysis, fatty acid oxidation, and amino acid metabolism, determine vasculature formation. These metabolic pathways have different roles in securing the production of energy and biomass and the maintenance of redox homeostasis in vascular migratory tip cells, proliferating stalk cells, and quiescent phalanx cells, respectively. Emerging evidence demonstrates that perturbation of EC metabolism results in EC dysfunction and vascular pathologies. Here, we summarize recent insights into EC metabolic pathways and their deregulation in vascular diseases. We further discuss the therapeutic implications of targeting EC metabolism in various pathologies.

scholarly journals The anti-angiogenic compound dimethyl fumarate inhibits the serine synthesis pathway and increases glycolysis in endothelial cells

2021 ◽  
Author(s):  
Maria Carmen Ocana ◽  
Chendong Yang ◽  
Manuel Bernal ◽  
Beatriz Martinez-Poveda ◽  
Hieu S. Vu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Essential Feature ◽  
Cell Metabolism ◽  
Krebs Cycle ◽  
Dimethyl Fumarate ◽  
Angiogenic Switch ◽  
Glycine Synthesis

A pathological and persistent angiogenesis is observed in several diseases like retinopathies, diabetes, psoriasis and cancer. Dimethyl fumarate, an ester from the Krebs cycle intermediate fumarate, is approved as a drug for the treatment of psoriasis and multiple sclerosis, and its anti-angiogenic activity has been reported in vitro and in vivo. However, it is not known whether dimethyl fumarate is able to modulate endothelial cell metabolism, considered an essential feature for the angiogenic switch. By means of different experimental approximations, including proteomics, isotope tracing and metabolomics experimental approaches, in this work we studied the possible role of dimethyl fumarate in endothelial cell energetic metabolism. We demonstrate for the first time that dimethyl fumarate promotes glycolysis and diminishes cell respiration, which could be a consequence of a down-regulation of serine and glycine synthesis through inhibition of PHGDH activity in endothelial cells. This new target can open a new field of study regarding the mechanism of action of dimethyl fumarate.

scholarly journals Glomerular endothelial cell fenestrations: an integral component of the glomerular filtration barrier

2009 ◽  
Vol 296 (5) ◽  
pp. F947-F956 ◽  
Author(s):  
Simon C. Satchell ◽  
Filip Braet
Keyword(s):  
Endothelial Cell ◽  
Glomerular Filtration ◽  
In Vitro Models ◽  
Glomerular Injury ◽  
Glomerular Endothelial Cell ◽  
Glomerular Filtration Barrier ◽  
Therapeutic Implications ◽  
Filtration Barrier ◽  
Glomerular Development

Glomerular endothelial cell (GEnC) fenestrations are analogous to podocyte filtration slits, but their important contribution to the glomerular filtration barrier has not received corresponding attention. GEnC fenestrations are transcytoplasmic holes, specialized for their unique role as a prerequisite for filtration across the glomerular capillary wall. Glomerular filtration rate is dependent on the fractional area of the fenestrations and, through the glycocalyx they contain, GEnC fenestrations are important in restriction of protein passage. Hence, dysregulation of GEnC fenestrations may be associated with both renal failure and proteinuria, and the pathophysiological importance of GEnC fenestrations is well characterized in conditions such as preeclampsia. Recent evidence suggests a wider significance in repair of glomerular injury and in common, yet serious, conditions, including diabetic nephropathy. Study of endothelial cell fenestrations is challenging because of limited availability of suitable in vitro models and by the requirement for electron microscopy to image these sub-100-nm structures. However, extensive evidence, from glomerular development in rodents to in vitro studies in human GEnC, points to vascular endothelial growth factor (VEGF) as a key inducer of fenestrations. In systemic endothelial fenestrations, the intracellular pathways through which VEGF acts to induce fenestrations include a key role for the fenestral diaphragm protein plasmalemmal vesicle-associated protein-1 (PV-1). The role of PV-1 in GEnC is less clear, not least because of controversy over existence of GEnC fenestral diaphragms. In this article, the structure-function relationships of GEnC fenestrations will be evaluated in depth, their role in health and disease explored, and the outlook for future study and therapeutic implications of these peculiar structures will be approached.

scholarly journals Lipid Catabolism and ROS in Cancer: A Bidirectional Liaison

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5484
Author(s):  
Serena Castelli ◽  
Pamela De De Falco ◽  
Fabio Ciccarone ◽  
Enrico Desideri ◽  
Maria Rosa Ciriolo
Keyword(s):  
Cancer Cells ◽  
Cell Metabolism ◽  
Second Messengers ◽  
Tumor Therapy ◽  
Redox Homeostasis ◽  
Antioxidant Systems ◽  
Acid Oxidation ◽  
Antioxidant Compounds ◽  
Tumor Type ◽  
Lipid Catabolism

Although cancer cell metabolism was mainly considered to rely on glycolysis, with the concomitant impairment of mitochondrial metabolism, it has recently been demonstrated that several tumor types are sustained by oxidative phosphorylation (OXPHOS). In this context, endogenous fatty acids (FAs) deriving from lipolysis or lipophagy are oxidised into the mitochondrion, and are used as a source of energy through OXPHOS. Because the electron transport chain is the main source of ROS, cancer cells relying on fatty acid oxidation (FAO) need to be equipped with antioxidant systems that maintain the ROS levels under the death threshold. In those conditions, ROS can act as second messengers, favouring proliferation and survival. Herein, we highlight the different responses that tumor cells adopt when lipid catabolism is augmented, taking into account the different ROS fates. Many papers have demonstrated that the pro- or anti-tumoral roles of endogenous FA usage are hugely dependent on the tumor type, and on the capacity of cancer cells to maintain redox homeostasis. In light of this, clinical studies have taken advantage of the boosting of lipid catabolism to increase the efficacy of tumor therapy, whereas, in other contexts, antioxidant compounds are useful to reduce the pro-survival effects of ROS deriving from FAO.

scholarly journals Therapeutic Implications of Targeting Heat Shock Protein 70 by Immunization or Antibodies in Experimental Skin Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Stefan Tukaj ◽  
Jagoda Mantej ◽  
Michał Sobala ◽  
Katarzyna Potrykus ◽  
Zbigniew Tukaj ◽  
...  
Keyword(s):  
T Cells ◽  
Heat Shock ◽  
Skin Inflammation ◽  
Antibody Treatment ◽  
Therapeutic Implications ◽  
Promising Therapeutic Target ◽  
Shock Proteins ◽  
Autoimmune Dermatoses

Heat shock proteins (Hsp) are constitutive and stress-induced molecules which have been reported to impact innate and adaptive immune responses. Here, we evaluated the role of Hsp70 as a treatment target in the imiquimod-induced, psoriasis-like skin inflammation mouse model and related in vitro assays. We found that immunization of mice with Hsp70 resulted in decreased clinical and histological disease severity associated with expansion of T cells in favor of regulatory subtypes (CD4+FoxP3+/CD4+CD25+ cells). Similarly, anti-Hsp70 antibody treatment led to lowered disease activity associated with down-regulation of pro-inflammatory Th17 cells. A direct stimulating action of Hsp70 on regulatory T cells and its anti-proliferative effects on keratinocytes were confirmed in cell culture experiments. Our observations suggest that Hsp70 may be a promising therapeutic target in psoriasis and potentially other autoimmune dermatoses.

scholarly journals Hallmarks of Endothelial Cell Metabolism in Health and Disease

2019 ◽  
Vol 30 (3) ◽  
pp. 414-433 ◽  
Author(s):  
Xuri Li ◽  
Xiaodong Sun ◽  
Peter Carmeliet
Keyword(s):  
Endothelial Cell ◽  
Cell Metabolism ◽  
Health And Disease ◽  
Endothelial Cell Metabolism

scholarly journals Endothelial cell metabolism in health and disease: impact of hypoxia

2017 ◽  
Vol 36 (15) ◽  
pp. 2187-2203 ◽  
Author(s):  
Brian W Wong ◽  
Elke Marsch ◽  
Lucas Treps ◽  
Myriam Baes ◽  
Peter Carmeliet
Keyword(s):  
Endothelial Cell ◽  
Cell Metabolism ◽  
Health And Disease ◽  
Disease Impact ◽  
Endothelial Cell Metabolism

scholarly journals Endothelial Cell Metabolism in Health and Disease

2018 ◽  
Vol 28 (3) ◽  
pp. 224-236 ◽  
Author(s):  
Katerina Rohlenova ◽  
Koen Veys ◽  
Ines Miranda-Santos ◽  
Katrien De Bock ◽  
Peter Carmeliet
Keyword(s):  
Endothelial Cell ◽  
Cell Metabolism ◽  
Health And Disease ◽  
Endothelial Cell Metabolism

Effect of endothelial cell denudation on fatty acid metabolism by rabbit aorta

1990 ◽  
Vol 259 (2) ◽  
pp. H442-H447
Author(s):  
I. Takasaki ◽  
R. A. Cohen ◽  
A. V. Chobanian ◽  
P. Brecher
Keyword(s):  
Arachidonic Acid ◽  
Fatty Acid ◽  
Endothelial Cell ◽  
Vascular Endothelial Cells ◽  
Rabbit Aorta ◽  
Acid Oxidation ◽  
Acid Uptake ◽  
Cotton Swab ◽  
Acid Esterification

The potential regulatory role of vascular endothelial cells in fatty acid uptake and metabolism by arterial tissue was studied in vitro using aortic segments from New Zealand White rabbits. Endothelium was left intact or was removed either by scraping with forceps or by rubbing with a cotton swab. Aortic segments were incubated with [14C]oleate or [14C]arachidonate, and oxidation and esterification were measured. Endothelial cell denudation by forceps or cotton swab caused a decrease in oxidation of both oleic and arachidonic acid. Esterification of oleic and arachidonic acid into phospholipid was also significantly reduced by removing the endothelium; the percent reduction was less when endothelium was removed by cotton swab than it was by forceps. Incorporation into phospholipid was reduced by cotton swab treatment, but incorporation into triglyceride was unaffected. Forceps treatment reduced oleic acid esterification into both triglyceride and phospholipid. The studies suggest that arterial endothelium has a role in fatty acid oxidation and esterification and that fatty acid utilization may be a useful metabolic index of vascular injury.

scholarly journals LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Francesco Ciccarese ◽  
Elisabetta Zulato ◽  
Stefano Indraccolo
Keyword(s):  
Cellular Response ◽  
Cell Metabolism ◽  
Redox Homeostasis ◽  
Suppressor Gene ◽  
Ampk Signaling ◽  
Promising Therapeutic Target ◽  
Liver Kinase B1 ◽  
Nsclc Patients ◽  
Tumor Types

Inactivating mutations of the tumor suppressor gene Liver Kinase B1 (LKB1) are frequently detected in non-small-cell lung cancer (NSCLC) and cervical carcinoma. Moreover, LKB1 expression is epigenetically regulated in several tumor types. LKB1 has an established function in the control of cell metabolism and oxidative stress. Clinical and preclinical studies support a role of LKB1 as a central modifier of cellular response to different stress-inducing drugs, suggesting LKB1 pathway as a highly promising therapeutic target. Loss of LKB1-AMPK signaling confers sensitivity to energy depletion and to redox homeostasis impairment and has been associated with an improved outcome in advanced NSCLC patients treated with chemotherapy. In this review, we provide an overview of the interplay between LKB1 and its downstream targets in cancer and focus on potential therapeutic strategies whose outcome could depend from LKB1.

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