The Experts below are selected from a list of 4185 Experts worldwide ranked by ideXlab platform
Peter Carmeliet - One of the best experts on this subject based on the ideXlab platform.
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Metabolic Signatures of Distinct Endothelial Phenotypes
Trends in endocrinology and metabolism: TEM, 2020Co-Authors: Sébastien J. Dumas, Melissa García-caballero, Peter CarmelietAbstract:Angiogenesis is crucial for the development of the blood vasculature during embryogenesis, but also contributes to cancer and other diseases. While therapeutic targeting of endothelial cells (ECs) through growth factor inhibition is limited by insufficient efficacy and resistance, a new paradigm for modulating angiogenesis by targeting EC metabolism has emerged. Findings from the past decade highlight how ECs adapt their metabolism to proliferate or migrate during Vessel Sprouting, or to maintain the vascular barrier and protect themselves against oxidative stress in the high-oxygen environment they are exposed to in healthy conditions. We overview key endothelial metabolic pathways underlying the different EC phenotypes, as well as potential opportunities for targeting EC metabolism in therapeutic settings.
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Hallmarks of Endothelial Cell Metabolism in Health and Disease.
Cell metabolism, 2019Co-Authors: Xiaodong Sun, Peter CarmelietAbstract:In 2009, it was postulated that endothelial cells (ECs) would only be able to execute the orders of growth factors if these cells would accordingly adapt their metabolism. Ten years later, it has become clear that ECs, often differently from other cell types, rely on distinct metabolic pathways to survive and form new blood Vessels; that manipulation of EC metabolic pathways alone (even without changing angiogenic signaling) suffices to alter Vessel Sprouting; and that perturbations of these metabolic pathways can underlie excess formation of new blood Vessels (angiogenesis) in cancer and ocular diseases. Initial proof of evidence has been provided that targeting (normalizing) these metabolic perturbations in diseased ECs and delivery of metabolites deserve increasing attention as novel therapeutic approaches for inhibiting or stimulating Vessel growth in multiple disorders.
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Angiogenesis revisited from a metabolic perspective: role and therapeutic implications of endothelial cell metabolism.
Open biology, 2017Co-Authors: Nihed Draoui, Pauline De Zeeuw, Peter CarmelietAbstract: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.
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How Endothelial Cells Adapt Their Metabolism to Form Vessels in Tumors.
Frontiers in immunology, 2017Co-Authors: Annalisa Zecchin, Charlotte Dubois, Joanna Kalucka, Peter CarmelietAbstract:Endothelial cells (ECs) line blood Vessels, i.e., vital conduits for oxygen and nutrient delivery to distant tissues. While mostly present as quiescent "phalanx" cells throughout adult life, ECs can rapidly switch to a migratory "tip" cell and a proliferative "stalk" cell, and sprout into avascular tissue to form new blood Vessels. The angiogenic switch has long been considered to be primarily orchestrated by the activity of angiogenic molecules. However, recent evidence illustrates an instrumental role of cellular metabolism in Vessel Sprouting, whereby ECs require specific metabolic adaptations to grow. Here, we overview the emerging picture that tip, stalk, and phalanx cells have distinct metabolic signatures and discuss how these signatures can become deregulated in pathological conditions, such as in cancer.
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Endothelial cell metabolism: an update anno 2017.
Current opinion in hematology, 2017Co-Authors: Laure-anne Teuwen, Nihed Draoui, Charlotte Dubois, Peter CarmelietAbstract:Endothelial cell metabolism has recently emerged as an important coregulator of angiogenesis and is therefore a promising new target in various angiogenesis-associated illnesses, like cancer. In this review, we discuss recent insights in endothelial cell metabolism in both physiological and pathological conditions and discuss possible translational implications. Two metabolic pathways that determine the performance of endothelial cells are glycolysis and fatty acid oxidation (FAO). Glycolysis is essential as endothelial cells primarily rely on this pathway for ATP production. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) is a key regulator of glycolysis in endothelial cells. As endothelial cells increase glycolysis even further during angiogenesis, PFKFB3 also controls Vessel Sprouting and promotes endothelial cell migration. Moreover, in tumors, additional PFKFB3 upregulation leads to a more immature and dysfunctional vasculature. PFKFB3 blockade therefore results in tumor Vessel normalization, with beneficial therapeutic effects on reduced metastasis and improved chemotherapy. Also, FAO stimulates endothelial cell proliferation through affecting DNA synthesis, and is critical for lymphangiogenesis, in part through epigenetic changes in histone acetylation. As FAO is controlled by carnitine palmitoyltransferase 1a, inhibition of this key enzyme decreases pathological angiogenesis. Both PFKFB3 and carnitine palmitoyltransferase 1a are key metabolic regulators of Vessel Sprouting and promising new therapeutic targets in diseases associated with pathological angiogenesis.
Victoria L. Bautch - One of the best experts on this subject based on the ideXlab platform.
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excess centrosomes disrupt endothelial cell migration via centrosome scattering
Journal of Cell Biology, 2014Co-Authors: Erich J Kushner, Luke S Ferro, Andrew C. Dudley, Stephen L Rogers, Jessica R Durrant, Victoria L. BautchAbstract:Supernumerary centrosomes contribute to spindle defects and aneuploidy at mitosis, but the effects of excess centrosomes during interphase are poorly understood. In this paper, we show that interphase endothelial cells with even one extra centrosome exhibit a cascade of defects, resulting in disrupted cell migration and abnormal blood Vessel Sprouting. Endothelial cells with supernumerary centrosomes had increased centrosome scattering and reduced microtubule (MT) nucleation capacity that correlated with decreased Golgi integrity and randomized vesicle trafficking, and ablation of excess centrosomes partially rescued these parameters. Mechanistically, tumor endothelial cells with supernumerary centrosomes had less centrosome-localized γ-tubulin, and Plk1 blockade prevented MT growth, whereas overexpression rescued centrosome γ-tubulin levels and centrosome dynamics. These data support a model whereby centrosome–MT interactions during interphase are important for centrosome clustering and cell polarity and further suggest that disruption of interphase cell behavior by supernumerary centrosomes contributes to pathology independent of mitotic effects.
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Regulation of blood Vessel Sprouting.
Seminars in cell & developmental biology, 2011Co-Authors: John C. Chappell, David M. Wiley, Victoria L. BautchAbstract:Blood Vessels are essential conduits of nutrients and oxygen throughout the body. The formation of these Vessels involves angiogenic Sprouting, a complex process entailing highly integrated cell behaviors and signaling pathways. In this review, we discuss how endothelial cells initiate a Vessel sprout through interactions with their environment and with one another, particularly through lateral inhibition. We review the composition of the local environment, which contains an initial set of guidance cues to facilitate the proper outward migration of the sprout as it emerges from a parent Vessel. The long-range guidance and sprout stability cues provided by soluble molecules, extracellular matrix components, and interactions with other cell types are also discussed. We also examine emerging evidence for mechanisms that govern sprout fusion with its target and lumen formation.
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How Blood Vessel Networks Are Made and Measured
Cells tissues organs, 2011Co-Authors: John C. Chappell, David M. Wiley, Victoria L. BautchAbstract:Tissue and organ viability depends on the proper systemic distribution of cells, nutrients, and oxygen through blood Vessel networks. These networks arise in part via angiogenic Sprouting. Vessel Sprouting involves the precise coordination of several endothelial cell processes including cell-cell communication, cell migration, and proliferation. In this review, we discuss zebrafish and mammalian models of blood Vessel Sprouting and the quantification methods used to assess Vessel Sprouting and network formation in these models. We also review the mechanisms involved in angiogenic Sprouting, and we propose that the process consists of distinct stages. Sprout initiation involves endothelial cell interactions with neighboring cells and the environment to establish a specialized tip cell responsible for leading the emerging sprout. Furthermore, local sprout guidance cues that spatially regulate this outward migration are discussed. We also examine subsequent events, such as sprout fusion and lumenization, that lead to maturation of a nascent sprout into a patent blood Vessel.
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Ups and Downs of Guided Vessel Sprouting: The Role of Polarity
Physiology, 2011Co-Authors: Christina Y. Lee, Victoria L. BautchAbstract:Blood Vessel networks expand to meet oxygen demands via Sprouting angiogenesis. This process is heterogeneous but not random; as sprouts form and extend, neighboring endothelial cells do not sprout but divide. Sprouting is regulated by local sprout guidance cues produced by the Vessels themselves, as well as extrinsic cues. Endothelial cells in developing Vessels orient in several axes to establish migratory polarity, apical-basolateral polarity, and planar cell polarity. Although little is known about how polarity axes are set up or maintained, they are important for Vessel formation and function. This review focuses on the current knowledge of how blood Vessel Sprouting is regulated and guided, the role of endothelial cell polarity in forming Vessels, and how these processes affect Vessel function and are potentially perturbed in pathologies with vascular components.
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Ups and downs of guided Vessel Sprouting: The role of polarity
Physiology (Bethesda Md.), 2011Co-Authors: Christina Lee, Victoria L. BautchAbstract:Blood Vessel networks form via guided spouting, which involves heterogeneous responses to guidance cues and the establishment of different polarity axes.
Katrien De Bock - One of the best experts on this subject based on the ideXlab platform.
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Measuring Glycolytic and Mitochondrial Fluxes in Endothelial Cells Using Radioactive Tracers.
Methods in molecular biology (Clifton N.J.), 2018Co-Authors: Koen Veys, Abdiel Alvarado-diaz, Katrien De BockAbstract:Endothelial cells (ECs) form the inner lining of the vascular network. Although they can remain quiescent for years, ECs exhibit high plasticity in both physiological and pathological conditions, when they need to rapidly form new blood Vessels in a process called angiogenesis. EC metabolism recently emerged as an important driver of this angiogenic switch. The use of radioactive tracer substrates to assess metabolic flux rates in ECs has been essential for the discovery that fatty acid, glucose, and glutamine metabolism critically contribute to Vessel Sprouting. In the future, these assays will be useful as a tool for the characterization of pathological conditions in which deregulation of EC metabolism underlies and/or precedes the disease, but also for the identification of anti-angiogenic metabolic targets. This chapter describes in detail the radioactive tracer substrate assays that have been used for the determination of EC metabolic flux in vitro.
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partial and transient reduction of glycolysis by pfkfb3 blockade reduces pathological angiogenesis
Cell Metabolism, 2014Co-Authors: Sandra Schoors, Katrien De Bock, Anna Rita Cantelmo, Maria Georgiadou, Bart Ghesquiere, Sandra Cauwenberghs, Anna Kuchnio, Brian W Wong, Annelies Quaegebeur, Jermaine GoveiaAbstract:Strategies targeting pathological angiogenesis have focused primarily on blocking vascular endothelial growth factor (VEGF), but resistance and insufficient efficacy limit their success, mandating alternative antiangiogenic strategies. We recently provided genetic evidence that the glycolytic activator phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) promotes Vessel formation but did not explore the antiangiogenic therapeutic potential of PFKFB3 blockade. Here, we show that blockade of PFKFB3 by the small molecule 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) reduced Vessel Sprouting in endothelial cell (EC) spheroids, zebrafish embryos, and the postnatal mouse retina by inhibiting EC proliferation and migration. 3PO also suppressed vascular hyperbranching induced by inhibition of Notch or VEGF receptor 1 (VEGFR1) and amplified the antiangiogenic effect of VEGF blockade. Although 3PO reduced glycolysis only partially and transiently in vivo, this sufficed to decrease pathological neovascularization in ocular and inflammatory models. These insights may offer therapeutic antiangiogenic opportunities.
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role of endothelial cell metabolism in Vessel Sprouting
Cell Metabolism, 2013Co-Authors: Katrien De Bock, Maria Georgiadou, Peter CarmelietAbstract:Endothelial cells (ECs) are quiescent for years but can plastically switch to angiogenesis. Vascular Sprouting relies on the coordinated activity of migrating tip cells at the forefront and proliferating stalk cells that elongate the sprout. Past studies have identified genetic signals that control vascular branching. Prominent are VEGF, activating tip cells, and Notch, which stimulates stalk cells. After the branch is formed and perfused, ECs become quiescent phalanx cells. Now, emerging evidence has accumulated indicating that ECs not only adapt their metabolism when switching from quiescence to Sprouting but also that metabolism regulates vascular Sprouting in parallel to the control by genetic signals.
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Control of Vessel Sprouting by genetic and metabolic determinants.
Trends in endocrinology and metabolism: TEM, 2013Co-Authors: Guy Eelen, Katrien De Bock, Bert Cruys, Jonathan Welti, Peter CarmelietAbstract:Vessel Sprouting by endothelial cells (ECs) during angiogenesis relies on a navigating tip cell and on proliferating stalk cells that elongate the shaft. To date, only genetic signals have been shown to regulate Vessel Sprouting. However, emerging evidence indicates that the angiogenic switch also requires a metabolic switch. Indeed, angiogenic signals not only induce a change in EC metabolism but this metabolic adaptation also co-determines Vessel Sprouting. The glycolytic activator PFKFB3 regulates stalk cell proliferation and renders ECs more competitive to reach the tip. We discuss the emerging link between angiogenesis and EC metabolism during the various stages of Vessel Sprouting, focusing only on genetic signals for which an effect on EC metabolism has been documented.
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role of pfkfb3 driven glycolysis in Vessel Sprouting
Cell, 2013Co-Authors: Katrien De Bock, Sandra Schoors, Anna Rita Cantelmo, Maria Georgiadou, Bart Ghesquiere, Sandra Cauwenberghs, Anna Kuchnio, Brian W Wong, Annelies Quaegebeur, Guy EelenAbstract:Vessel Sprouting by migrating tip and proliferating stalk endothelial cells (ECs) is controlled by genetic signals (such as Notch), but it is unknown whether metabolism also regulates this process. Here, we show that ECs relied on glycolysis rather than on oxidative phosphorylation for ATP production and that loss of the glycolytic activator PFKFB3 in ECs impaired Vessel formation. Mechanistically, PFKFB3 not only regulated EC proliferation but also controlled the formation of filopodia/lamellipodia and directional migration, in part by compartmentalizing with F-actin in motile protrusions. Mosaic in vitro and in vivo Sprouting assays further revealed that PFKFB3 overexpression overruled the pro-stalk activity of Notch, whereas PFKFB3 deficiency impaired tip cell formation upon Notch blockade, implying that glycolysis regulates Vessel branching.
Donald M Mcdonald - One of the best experts on this subject based on the ideXlab platform.
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reduced vegf production angiogenesis and vascular regrowth contribute to the antitumor properties of dual mtorc1 mtorc2 inhibitors
Cancer Research, 2011Co-Authors: Beverly L Falcon, Sharon Barr, Prafulla C Gokhale, Jeyling Chou, Jennifer Fogarty, Philippe Depeille, Mark Miglarese, David Epstein, Donald M McdonaldAbstract:The mammalian target of rapamycin (mTOR) pathway is implicated widely in cancer pathophysiology. Dual inhibition of the mTOR kinase complexes mTORC1 and mTORC2 decreases tumor xenograft growth in vivo and VEGF secretion in vitro, but the relationship between these two effects are unclear. In this study, we examined the effects of mTORC1/2 dual inhibition on VEGF production, tumor angiogenesis, vascular regression, and vascular regrowth, and we compared the effects of dual inhibition to mTORC1 inhibition alone. ATP-competitive inhibitors OSI-027 and OXA-01 targeted both mTORC1 and mTORC2 signaling in vitro and in vivo, unlike rapamycin that only inhibited mTORC1 signaling. OXA-01 reduced VEGF production in tumors in a manner associated with decreased Vessel Sprouting but little vascular regression. In contrast, rapamycin exerted less effect on tumoral production of VEGF. Treatment with the selective VEGFR inhibitor OSI-930 reduced Vessel Sprouting and caused substantial vascular regression in tumors. However, following discontinuation of OSI-930 administration tumor regrowth could be slowed by OXA-01 treatment. Combining dual inhibitors of mTORC1 and mTORC2 with a VEGFR2 inhibitor decreased tumor growth more than either inhibitor alone. Together, these results indicate that dual inhibition of mTORC1/2 exerts antiangiogenic and antitumoral effects that are even more efficacious when combined with a VEGFR antagonist.
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Reduced VEGF Production, Angiogenesis, and Vascular Regrowth Contribute to the Antitumor Properties of Dual mTORC1/mTORC2 Inhibitors
Cancer research, 2011Co-Authors: Beverly L Falcon, Sharon Barr, Prafulla C Gokhale, Jeyling Chou, Jennifer Fogarty, Philippe Depeille, Mark Miglarese, David Epstein, Donald M McdonaldAbstract:The mammalian target of rapamycin (mTOR) pathway is implicated widely in cancer pathophysiology. Dual inhibition of the mTOR kinase complexes mTORC1 and mTORC2 decreases tumor xenograft growth in vivo and VEGF secretion in vitro, but the relationship between these two effects are unclear. In this study, we examined the effects of mTORC1/2 dual inhibition on VEGF production, tumor angiogenesis, vascular regression, and vascular regrowth, and we compared the effects of dual inhibition to mTORC1 inhibition alone. ATP-competitive inhibitors OSI-027 and OXA-01 targeted both mTORC1 and mTORC2 signaling in vitro and in vivo, unlike rapamycin that only inhibited mTORC1 signaling. OXA-01 reduced VEGF production in tumors in a manner associated with decreased Vessel Sprouting but little vascular regression. In contrast, rapamycin exerted less effect on tumoral production of VEGF. Treatment with the selective VEGFR inhibitor OSI-930 reduced Vessel Sprouting and caused substantial vascular regression in tumors. However, following discontinuation of OSI-930 administration tumor regrowth could be slowed by OXA-01 treatment. Combining dual inhibitors of mTORC1 and mTORC2 with a VEGFR2 inhibitor decreased tumor growth more than either inhibitor alone. Together, these results indicate that dual inhibition of mTORC1/2 exerts antiangiogenic and antitumoral effects that are even more efficacious when combined with a VEGFR antagonist.
Shane P. Herbert - One of the best experts on this subject based on the ideXlab platform.
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mRNA localisation in endothelial cells regulates blood Vessel Sprouting
2018Co-Authors: Guilherme Costa, Nawseen Tarannum, Shane P. HerbertAbstract:The subcellular distribution of mRNAs is a fundamental biological mechanism implicated in the spatial regulation of gene expression in many cellular contexts. However, whether mRNA localisation contributes to complex morphogenetic processes underpinning tissue development remains unknown. We focused on a model transcript, RAB13, and demonstrated how it is preferentially localised to and locally translated at the leading edge of migrating endothelial cells. We generated a novel MS2-GFPnls zebrafish reporter strain and use the 3′ UTR of RAB13 to show, for the first time, tissue-specific visualisation of a localised RNA in migratory cell processes in a living vertebrate organism. Moreover, after mutating the endogenous 3′ UTR of RAB13 to disrupt transcript localisation in-vivo, we report altered formation of endothelial cell protrusions within Sprouting Vessels. Hence, we demonstrate the involvement of mRNA localisation in endothelial cell migration during angiogenesis and are the first to reveal that subcellular transcript distribution modulates tissue morphogenesis.
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molecular control of endothelial cell behaviour during blood Vessel morphogenesis
Nature Reviews Molecular Cell Biology, 2011Co-Authors: Shane P. Herbert, Didier Y R StainierAbstract:The vertebrate vasculature forms an extensive branched network of blood Vessels that supplies tissues with nutrients and oxygen. During vascular development, coordinated control of endothelial cell behaviour at the levels of cell migration, proliferation, polarity, differentiation and cell-cell communication is critical for functional blood Vessel morphogenesis. Recent data uncover elaborate transcriptional, post-transcriptional and post-translational mechanisms that fine-tune key signalling pathways (such as the vascular endothelial growth factor and Notch pathways) to control endothelial cell behaviour during blood Vessel Sprouting (angiogenesis). These emerging frameworks controlling angiogenesis provide unique insights into fundamental biological processes common to other systems, such as tissue branching morphogenesis, mechanotransduction and tubulogenesis.
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molecular control of endothelial cell behaviour during blood Vessel morphogenesis
Nature Reviews Molecular Cell Biology, 2011Co-Authors: Shane P. Herbert, Didier Y R StainierAbstract:The coordinated control of endothelial cell behaviour is critical for blood Vessel morphogenesis. Recent data reveal elaborate mechanisms that fine-tune key signalling pathways (such as the vascular endothelial growth factor and Notch pathways) to control endothelial cell behaviour during blood Vessel Sprouting (angiogenesis).
