scholarly journals FGFR Signaling Coordinates the Balance Between Glycolysis and Fatty Acid β-Oxidation in Lymphatic Endothelial Cells

2020 ◽  
Author(s):  
Hongyuan Song ◽  
Jie Zhu ◽  
Longhou Fang ◽  
Pengchun Yu
Keyword(s):  
Endothelial Cells ◽  
Fatty Acid ◽  
Growth Factor Receptor ◽  
Dependent Manner ◽  
Lymphatic Endothelial Cells ◽  
Energy Deficiency ◽  
Atp Production ◽  
Atp Generation ◽  
And Migration ◽  
A Minor

AbstractThe balance between glycolysis and oxidative phosphorylation is believed to be critical for maintaining cellular bioenergetics, yet the regulation of such balance in lymphatic endothelial cells (LECs) remains unclear. Here we found that chemical inhibition of fibroblast growth factor receptor (FGFR) activity or knockdown of FGFR1, which has been shown to suppress glycolysis and consequently ATP production, induces substantial upregulation of fatty acid β-oxidation (FAO), but not glucose oxidation or glutamine oxidation in LECs. Mechanistically, blockade of FGFR-AKT signaling promotes the expression of CPT1A, a rate-limiting enzyme of FAO, in a PPARα-dependent manner. Metabolic analysis further showed that CPT1A depletion impairs ATP generation in FGFR1-deficient rather than wild-type LECs. This result suggests that FAO, which makes a minor contribution to cellular energy under normal conditions, can compensate for energy deficiency caused by FGFR inhibition. Consequently, CPT1A silencing potentiates the effect of FGFR1 knockdown on impeding LEC proliferation and migration. Collectively, our study identified an FGFR-regulated metabolic balance that is important for LEC growth.

scholarly journals Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-κB and Prox1

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. 418-429 ◽  
Author(s):  
Michael J. Flister ◽  
Andrew Wilber ◽  
Kelly L. Hall ◽  
Caname Iwata ◽  
Kohei Miyazono ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Lymphatic Vessels ◽  
Growth Factor Receptor ◽  
Receptor Expression ◽  
Lymphatic Endothelial Cells ◽  
Inflammatory Stimuli ◽  
And Migration

Abstract The concept of inflammation-induced lymphangiogenesis (ie, formation of new lymphatic vessels) has long been recognized, but the molecular mechanisms remained largely unknown. The 2 primary mediators of lymphangiogenesis are vascular endothelial growth factor receptor-3 (VEGFR-3) and Prox1. The key factors that regulate inflammation-induced transcription are members of the nuclear factor-kappaB (NF-κB) family; however, the role of NF-κB in regulation of lymphatic-specific genes has not been defined. Here, we identified VEGFR-3 and Prox1 as downstream targets of the NF-κB pathway. In vivo time-course analysis of inflammation-induced lymphangiogenesis showed activation of NF-κB followed by sequential up-regulation of Prox1 and VEGFR-3 that preceded lymphangiogenesis by 4 and 2 days, respectively. Activation of NF-κB by inflammatory stimuli also elevated Prox1 and VEGFR-3 expression in cultured lymphatic endothelial cells, resulting in increased proliferation and migration. We also show that Prox1 synergizes with the p50 of NF-κB to control VEGFR-3 expression. Collectively, our findings suggest that induction of the NF-κB pathway by inflammatory stimuli activates Prox1, and both NF-κB and Prox1 activate the VEGFR-3 promoter leading to increased receptor expression in lymphatic endothelial cells. This, in turn, enhances the responsiveness of preexisting lymphatic endothelium to VEGFR-3 binding factors, VEGF-C and VEGF-D, ultimately resulting in robust lymphangiogenesis.

scholarly journals Characterization of the mechanisms involved in the early specification and migration of Prox1-expressing lymphatic endothelial cells

2011 ◽  
Vol 356 (1) ◽  
pp. 171
Author(s):  
Ying Yang ◽  
Kimberle Shen ◽  
Sathish Srinivasan ◽  
Amira Masri ◽  
Joshua Scallan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Endothelial Cells ◽  
And Migration

scholarly journals Isolation and Characterisation of Lymphatic Endothelial Cells from Lung Tissues Affected by Lymphangioleiomyomatosis

2021 ◽  
Author(s):  
Koichi Nishino ◽  
Yasuhiro Yoshimatsu ◽  
Tomoki Muramatsu ◽  
Yasuhito Sekimoto ◽  
Keiko Mitani ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Normal Lung ◽  
Vascular Endothelial ◽  
Lymphatic Endothelial Cells ◽  
And Migration ◽  
Endothelial Growth Factor ◽  
Proliferation And Migration

Abstract Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease characterised by the proliferation of smooth muscle-like cells (LAM cells), and an abundance of lymphatic vessels in LAM lesions. Studies reported that vascular endothelial growth factor-D (VEGF-D) secreted by LAM cells contributes to LAM-associated lymphangiogenesis, however, the precise mechanisms of lymphangiogenesis and characteristics of lymphatic endothelial cells (LECs) in LAM lesions have not yet been elucidated. In this study, human primary-cultured LECs were obtained both from LAM-affected lung tissues (LAM-LECs) and normal lung tissues (control LECs) using fluorescence-activated cell sorting (FACS). We found that LAM-LECs had significantly higher ability of proliferation and migration compared to control LECs. VEGF-D significantly promoted migration of LECs but not proliferation of LECs in vitro. cDNA microarray and FACS analysis revealed the expression of vascular endothelial growth factor receptor (VEGFR)-3 and integrin α9 were elevated in LAM-LECs. Inhibition of VEGFR-3 suppressed proliferation and migration of LECs, and blockade of integrin α9 reduced VEGF-D-induced migration of LECs. Our data uncovered the distinct features of LAM-associated LECs, increased proliferation and migration, which may be due to higher expression of VEGFR-3 and integrin α9. Furthermore, we also found VEGF-D/VEGFR-3 and VEGF-D/ integrin α9 signaling play an important role in LAM-associated lymphangiogenesis.

scholarly journals REDD1 is a determinant of low-dose metronomic doxorubicin-elicited endothelial cell dysfunction through downregulation of VEGFR-2/3 expression

2021 ◽  
Author(s):  
Minsik Park ◽  
Joohwan Kim ◽  
Taesam Kim ◽  
Suji Kim ◽  
Wonjin Park ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Tumor Angiogenesis ◽  
Low Dose ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Metronomic Chemotherapy ◽  
Endothelial Cell Dysfunction ◽  
Lymphatic Endothelial Cells ◽  
Cell Dysfunction

AbstractLow-dose metronomic chemotherapy (LDMC) inhibits tumor angiogenesis and growth by targeting tumor-associated endothelial cells, but the molecular mechanism has not been fully elucidated. Here, we examined the functional role of regulated in development and DNA damage responses 1 (REDD1), an inhibitor of mammalian target of rapamycin complex 1 (mTORC1), in LDMC-mediated endothelial cell dysfunction. Low-dose doxorubicin (DOX) treatment induced REDD1 expression in cultured vascular and lymphatic endothelial cells and subsequently repressed the mRNA expression of mTORC1-dependent translation of vascular endothelial growth factor receptor (Vegfr)-2/3, resulting in the inhibition of VEGF-mediated angiogenesis and lymphangiogenesis. These regulatory effects of DOX-induced REDD1 expression were additionally confirmed by loss- and gain-of-function studies. Furthermore, LDMC with DOX significantly suppressed tumor angiogenesis, lymphangiogenesis, vascular permeability, growth, and metastasis in B16 melanoma-bearing wild-type but not Redd1-deficient mice. Altogether, our findings indicate that REDD1 is a crucial determinant of LDMC-mediated functional dysregulation of tumor vascular and lymphatic endothelial cells by translational repression of Vegfr-2/3 transcripts, supporting the potential therapeutic properties of REDD1 in highly progressive or metastatic tumors.

scholarly journals A Comprehensive Assessment of Apigenin as an Antiproliferative, Proapoptotic, Antiangiogenic and Immunomodulatory Phytocompound

Nutrients ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 858 ◽  
Author(s):  
Alexandra Ghițu ◽  
Anja Schwiebs ◽  
Heinfried H. Radeke ◽  
Stefana Avram ◽  
Istvan Zupko ◽  
...  
Keyword(s):  
Comprehensive Evaluation ◽  
Annexin V ◽  
Dependent Manner ◽  
Experimental Conditions ◽  
Cell Growth And Migration ◽  
Atp Production ◽  
Lactate Dehydrogenase Release ◽  
High Concentrations ◽  
And Migration ◽  
Lps Activation

Apigenin (4′,5,7-trihydroxyflavone) (Api) is an important component of the human diet, being distributed in a wide number of fruits, vegetables and herbs with the most important sources being represented by chamomile, celery, celeriac and parsley. This study was designed for a comprehensive evaluation of Api as an antiproliferative, proapoptotic, antiangiogenic and immunomodulatory phytocompound. In the set experimental conditions, Api presents antiproliferative activity against the A375 human melanoma cell line, a G2/M arrest of the cell cycle and cytotoxic events as revealed by the lactate dehydrogenase release. Caspase 3 activity was inversely proportional to the Api tested doses, namely 30 μM and 60 μM. Phenomena of early apoptosis, late apoptosis and necrosis following incubation with Api were detected by Annexin V-PI double staining. The flavone interfered with the mitochondrial respiration by modulating both glycolytic and mitochondrial pathways for ATP production. The metabolic activity of human dendritic cells (DCs) under LPS-activation was clearly attenuated by stimulation with high concentrations of Api. Il-6 and IL-10 secretion was almost completely blocked while TNF alpha secretion was reduced by about 60%. Api elicited antiangiogenic properties in a dose-dependent manner. Both concentrations of Api influenced tumour cell growth and migration, inducing a limited tumour area inside the application ring, associated with a low number of capillaries.

scholarly journals Inhibitory effect of serotonin derivatives on high glucose-induced adhesion and migration of monocytes on human aortic endothelial cells

2009 ◽  
Vol 102 (2) ◽  
pp. 264-272 ◽  
Author(s):  
Rosaria Piga ◽  
Yuji Naito ◽  
Satoshi Kokura ◽  
Osamu Handa ◽  
Toshikazu Yoshikawa
Keyword(s):  
Endothelial Cells ◽  
High Glucose ◽  
Atherosclerotic Lesion ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Aortic Endothelial Cells ◽  
Serotonin Derivatives ◽  
And Migration ◽  
Human Aortic Endothelial Cells ◽  
Aortic Endothelial

Previous reports have shown that safflower-seed extract and its major antioxidant constituents, serotonin hydroxycinnamic amides, attenuated atherosclerotic lesion formation in apoE-deficient mice, as well as inflammation and aortic stiffness in human subjects. In the present report, we examined a still unknown cell-based mechanism of serotonin derivatives against the development of atherosclerosis, focusing our attention on their action against the increase of adhesion molecules and the release of chemotactic factors on human aortic endothelial cells, phenomena that represent the key events in the early stages of atherosclerogenesis. Serotonin derivatives N-(p-coumaroyl)serotonin and N-feruloylserotonin exerted an inhibitory effect on short-term high glucose-induced up-regulation of mRNA and protein of adhesion and migration factors, and the consequent adhesion and migration of monocytes to endothelial cells; they inhibited the activation of transcription factors such as NF-κB, and the overproduction of the mitochondrial superoxide by acting as scavengers of the superoxide radical. In addition, serotonin derivative concentration inside the cells and inside the mitochondria was increased in a time-dependent manner. These results identify a mechanism of action of serotonin derivatives against endothelial damage at a cellular level, and underline their benefits against the disorders and complications related to reactive oxygen species.

scholarly journals Bradykinin B2 Receptor Contributes to Inflammatory Responses in Human Endothelial Cells by the Transactivation of the Fibroblast Growth Factor Receptor FGFR-1

2018 ◽  
Vol 19 (9) ◽  
pp. 2638 ◽  
Author(s):  
Erika Terzuoli ◽  
Federico Corti ◽  
Ginevra Nannelli ◽  
Antonio Giachetti ◽  
Sandra Donnini ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Inflammatory Responses ◽  
Growth Factor Receptor ◽  
Cell Permeability ◽  
Fibroblast Growth ◽  
Endothelial Cell Permeability ◽  
And Migration

Elevated levels of bradykinin (BK) and fibroblast growth factor-2 (FGF-2) have been implicated in the pathogenesis of inflammatory and angiogenic disorders. In angiogenesis, both stimuli induce a pro-inflammatory signature in endothelial cells, activating an autocrine/paracrine amplification loop that sustains the neovascularization process. Here we investigated the contribution of the FGF-2 pathway in the BK-mediated human endothelial cell permeability and migration, and the role of the B2 receptor (B2R) of BK in this cross-talk. BK (1 µM) upregulated the FGF-2 expression and promoted the FGF-2 signaling, both in human umbilical vein endothelial cells (HUVEC) and in retinal capillary endothelial cells (HREC) by the activation of Fibroblast growth factor receptor-1 (FGFR-1) and its downstream signaling (fibroblast growth factor receptor substrate: FRSα, extracellular signal–regulated kinases1/2: ERK1/2, and signal transducer and activator of transcription 3: STAT3 phosphorylation). FGFR-1 phosphorylation triggered by BK was c-Src mediated and independent from FGF-2 upregulation. Either HUVEC and HREC exposed to BK showed increased permeability, disassembly of adherens and tight-junction, and increased cell migration. B2R blockade by the selective antagonist, fasitibant, significantly inhibited FGF-2/FGFR-1 signaling, and in turn, BK-mediated endothelial cell permeability and migration. Similarly, the FGFR-1 inhibitor, SU5402, and the knock-down of the receptor prevented the BK/B2R inflammatory response in endothelial cells. In conclusion, this work demonstrates the existence of a BK/B2R/FGFR-1/FGF-2 axis in endothelial cells that might be implicated in propagation of angiogenic/inflammatory responses. A B2R blockade, by abolishing the initial BK stimulus, strongly attenuated FGFR-1-driven cell permeability and migration.

Involvement of cell surface ATP synthase in flow-induced ATP release by vascular endothelial cells

2007 ◽  
Vol 293 (3) ◽  
pp. H1646-H1653 ◽  
Author(s):  
Kimiko Yamamoto ◽  
Nobutaka Shimizu ◽  
Syotaro Obi ◽  
Shinichiro Kumagaya ◽  
Yutaka Taketani ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Cell Surface ◽  
Lipid Rafts ◽  
Atp Synthase ◽  
Vascular Endothelial Cells ◽  
Atp Release ◽  
Dependent Manner ◽  
Caveolin 1 ◽  
Atp Generation

Endothelial cells (ECs) release ATP in response to shear stress, a mechanical force generated by blood flow, and the ATP released modulates EC functions through activation of purinoceptors. The molecular mechanism of the shear stress-induced ATP release, however, has not been fully elucidated. In this study, we have demonstrated that cell surface ATP synthase is involved in shear stress-induced ATP release. Immunofluorescence staining of human pulmonary arterial ECs (HPAECs) showed that cell surface ATP synthase is distributed in lipid rafts and co-localized with caveolin-1, a marker protein of caveolae. Immunoprecipitation indicated that cell surface ATP synthase and caveolin-1 are physically associated. Measurement of the extracellular metabolism of [3H]ADP confirmed that cell surface ATP synthase is active in ATP generation. When exposed to shear stress, HPAECs released ATP in a dose-dependent manner, and the ATP release was markedly suppressed by the membrane-impermeable ATP synthase inhibitors angiostatin and piceatannol and by an anti-ATP synthase antibody. Depletion of plasma membrane cholesterol with methyl-β-cyclodextrin (MβCD) disrupted lipid rafts and abolished co-localization of ATP synthase with caveolin-1, which resulted in a marked reduction in shear stress-induced ATP release. Pretreatment of the cells with cholesterol prevented these effects of MβCD. Downregulation of caveolin-1 expression by transfection of caveolin-1 siRNA also markedly suppressed ATP-releasing responses to shear stress. Neither MβCD, MβCD plus cholesterol, nor caveolin-1 siRNA had any effect on the amount of cell surface ATP synthase. These results suggest that the localization and targeting of ATP synthase to caveolae/lipid rafts is critical for shear stress-induced ATP release by HPAECs.

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