Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Suppression of ANGPTL4 Reprograms Endothelial Cell Metabolism and Inhibits Angiogenesis

ABSTRACT: Angiopoietin-like 4 (ANGPTL4) is known to regulate various cellular and systemic functions. However, its cell-specific role in endothelial cells (ECs) function and metabolic homeostasis remains to be elucidated. Here, using endothelial-specific Angptl4 knock-out mice (Angptl4iEC), and transcriptomics and metabolic flux analysis, we demonstrate that ANGPTL4 is required for maintaining EC metabolic function vital for vascular permeability and angiogenesis. Knockdown of ANGPTL4 in ECs promotes lipase-mediated lipoprotein lipolysis, which results in increased fatty acid (FA) uptake and oxidation. This is also paralleled by a decrease in proper glucose utilization for angiogenic activation of ECs. Mice with endothelial-specific deletion of Angptl4 showed decreased pathological neovascularization with stable vessel structures characterized by increased pericyte coverage and reduced permeability. Together, our study denotes the role of endothelial-ANGPTL4 in regulating cellular metabolism and angiogenic functions of EC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE211128 | GEO | 2023/11/22

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Endothelial cell heterogeneity in pathological angiogenesis characterized by metabolic transcriptome diversity

Project description:Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor and choroidal neovascularization (CNV), but little is known about individual EC metabolic transcrip-tomes. Here, by scRNA-sequencing 28,337 murine choroidal ECs (CECs) and sprouting CNV-ECs, we constructed a taxonomy to characterize their heterogeneity. Comparison with murine lung tumor ECs (TECs) revealed congruent marker gene expression by distinct EC phenotypes across tissues and diseases, suggesting similar angiogenic mechanisms. Trajectory inference of CNV-ECs revealed that differentiation of venous to angiogenic ECs was accompanied by metabolic transcriptome plasticity. EC phenotypes displayed metabolic transcriptome heterogeneity. Hypothesizing that conserved genes are more important, we used an integrated analysis, based on congruent transcriptome analysis, CEC-tailored genome scale metabolic modeling, and gene expression me-ta-analysis in multiple cross-species datasets, followed by functional validation, to identify the top-ranking metabolic targets SQLE and ALDH18A1, involved in EC proliferation and collagen production, respectively, as novel angiogenic targets.

2020-03-31 | E-MTAB-8604 | biostudies-arrayexpress

Endothelial metabolic transcriptome plasticity in pathological angiogenesis

Project description:Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor and choroidal neovascularization (CNV), but little is known about individual EC metabolic transcriptomes. Here, by scRNA-sequencing 28,337 murine choroidal ECs (CECs) and sprouting CNV-ECs, we constructed a taxonomy to characterize their heterogeneity. Comparison with murine lung tumor ECs (TECs) revealed congruent marker gene expression by distinct EC phenotypes across tissues and diseases, suggesting similar angiogenic mechanisms. Trajectory inference of CNV-ECs revealed that differentiation of venous to angiogenic ECs was accompanied by metabolic transcriptome plasticity. EC phenotypes displayed metabolic transcriptome heterogeneity. Hypothesizing that conserved genes are more important, we used an integrated analysis, based on congruent transcriptome analysis, CEC-tailored genome scale metabolic modeling, and gene expression meta-analysis in multiple cross-species datasets, followed by functional validation, to identify the top-ranking metabolic targets SQLE and ALDH18A1, involved in EC proliferation and collagen production, respectively, as novel angiogenic targets. The effect of SQLE and ALDH18A1 silencing in ECs was investigated by transcriptomics and proteomics analysis.

2020-04-14 | PXD016678 | Pride

A single cell transcriptome atlas of murine endothelial cells

Project description:The heterogeneity of endothelial cells (ECs), lining blood vessels, across tissues remains incompletely inventoried. We constructed an atlas of >32,000 single-EC transcriptomic data from 11 tissues of the model organism Mus musculus. We propose a new classification of EC phenotypes based on transcriptome signatures and inferred putative biological features. We identified top-ranking markers for ECs from each tissue. ECs from different vascular beds (arteries, capillaries, veins, lymphatics) resembled each other across tissues, but only arterial, venous and lymphatic (not capillary) ECs shared markers, illustrating a greater heterogeneity of capillary ECs. We identified high-endothelial-venule and lacteal-like ECs in the intestines, and angiogenic ECs in healthy tissues. Metabolic transcriptomes of ECs differed amongst spleen, lung, liver, brain and testis, while being similar for kidney, heart, muscle and intestines. Within tissues, metabolic gene expression was heterogeneous amongst ECs from different vascular beds, altogether highlighting large EC heterogeneity.

2020-02-13 | E-MTAB-8077 | biostudies-arrayexpress

Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth

Project description:<p>The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer. </p>

2020-06-29 | MTBLS1764 | MetaboLights

Endothelial cell heterogeneity in pathological angiogenesis characterized by metabolic transcriptome diversity

Project description:Endothelial cell (EC) metabolism regulates angiogenesis and is an emerging target for anti-angiogenic therapy in tumor and choroidal neovascularization (CNV). In contrast to tumor ECs (TECs), CNV-ECs cannot be isolated for unbiased metabolic target discovery. Here we used scRNA-sequencing to profile 28,337 choroidal ECs (CECs) from mice to in silico distinguish healthy CECs from CNV-ECs. Trajectory inference suggested that CNV-ECs plastically upregulate genes in central carbon metabolism and collagen biosynthesis during differentiation from quiescent postcapillary venous ECs. CEC-tailored genome scale metabolic modeling predicted essentiality of SQLE and ALDH18A1 for proliferation and collagen production, respectively. Comparative analysis in TECs revealed more outspoken metabolic transcriptome heterogeneity in subtypes and consistent upregulation of SQLE and ALDH18A1 across tumor types. Inhibition of SQLE and ALDH18A1 reduced sprouting angiogenesis in vitro. These findings demonstrate the potential of integrated scRNA-seq analysis to identify angiogenic metabolic targets in disease ECs.

2020-06-25 | E-MTAB-8119 | biostudies-arrayexpress

A role for CPT1A to prevent blood vessel permeability revealed by in depth proteomics

Project description:Endothelial cells (ECs) line the inner wall of blood vessels and maintain vascular stability. Vascular stability alteration is a hallmark of pathologies such as cancer and thrombosis. A role for fatty acid oxidation (FAO) in this process is unknown. Integrating MS-proteomics and metabolic modeling revealed that FAO increases when ECs cultured on matrigel are assembled into a fully formed network. Inhibition of CPT1A in ECs, a limiting enzyme in FAO, results in disruption of this network. Acute CPT1A inhibition reduces cellular ATP levels and oxygen consumption, which can be restored replenishing the tricarboxylic acid cycle (TCAc). Phosphoproteomic changes upon acute CPT1A inhibition evoked those triggered by thrombin, a potent inducer of EC permeability through calcium signaling. Indeed, CPT1A inhibition increased EC permeability and vascular leakage, which were restored replenishing the TCAc or, partially, inhibiting calcium influx. Our study shows the possibility of altering FAO to interfere with ECs in diseases.

2015-01-28 | PXD001186 | Pride

Quiescent endothelial cells upregulate fatty acid β-oxidation for vasculoprotection via redox homeostasis

Project description:Little is known about metabolic changes accompanying endothelial cell (EC) quiescence. Nonetheless, when dysfunctional, quiescent ECs (QECs) contribute to multiple cardiovascular diseases. ECs need fatty acid β-oxidation (FAO) for proliferation. Surprisingly, we now report that QECs are not hypo-metabolic, but upregulate FAO >3-fold higher than proliferating ECs (PECs), not to support biomass or energy production, but to sustain the TCA cycle for redox homeostasis through NADPH production. Hence, inhibition of FAO-controlling CPT1A promotes EC dysfunction (anti-fibrinolysis, leukocyte infiltration, barrier disruption) by increasing oxidative stress in CPT1AΔEC mice with endothelial CPT1A loss. Mechanistically, Notch1 orchestrates the use of FAO for redox balance in QECs. Supplementation of acetate (metabolized to acetyl-CoA) induces vasculoprotection against oxidative stress and EC dysfunction in CPT1AΔEC mice, possibly creating therapeutic opportunities. Thus, ECs use FAO for vasculoprotection against their high oxygen (oxidative stress-prone) milieu, and for different metabolic purposes dependent on their proliferation versus quiescence status.

2018-09-12 | E-MTAB-6595 | biostudies-arrayexpress

Closing the mitochondrial permeability transition pore in hiPSC-derived endothelial cells induces glycocalyx formation and functional maturation.

Project description:Human induced pluripotent stem cells (hiPSCs) are used to study organogenesis and model disease as well as being developed for regenerative medicine. Endothelial cells are among the many cell types differentiated from hiPSC, but their maturation and stabilization fall short of that in adult endothelium. We examined whether shear stress alone or in combination with pericyte co-culture would induce flow alignment and maturation of hiPSC-derived endothelial cells (hiPSC-ECs) but found no effects comparable to those in primary microvascular EC. In addition, hiPSC-ECs lacked a luminal glycocalyx, critical for vasculature homeostasis, shear stress sensing and signalling. We noted however, that hiPSC-EC have dysfunctional mitochondrial permeability transition pores, resulting in reduced mitochondrial function and increased reactive oxygen species (ROS). Closure of these pores by cyclosporine-A improved EC mitochondrial function but also restored the glycocalyx such that alignment to flow took place. These indicated that mitochondrial maturation is required for proper hiPSC-EC functionality.

2019-12-14 | E-MTAB-8392 | biostudies-arrayexpress

Actively translating transcriptome (Ribotag) profiling of mouse retinal endothelial cells during postnatal development

Project description:Angiogenesis, a process mediating the expansion of vascular beds in many physiological and pathological settings, requires dynamic changes in endothelial cell (EC) behavior. The molecular mechanisms governing EC activity during different phases of vascular growth, remodeling, maturation, and quiescence remain elusive. Here, we have employed actively translating transcriptome analysis of mouse retinal ECs for the characterization of dynamic gene expression changes during postnatal development and the identification of critical angiogenic factors.

2020-08-28 | E-MTAB-5087 | biostudies-arrayexpress

Characterization of ANGPTL4 function in macrophages and adipocytes using Angptl4-knockout and Angptl4-hypomorphic mice

Project description:ANGPTL4 regulates plasma lipids, making it an attractive target for correcting dyslipidemia. However, ANGPTL4 inactivation in mice fed a high fat diet causes chylous ascites, an acute-phase response, and mesenteric lymphadenopathy. Here, we studied the role of ANGPTL4 in lipid uptake in macrophages and in the above-mentioned pathologies using Angptl4-hypomorphic and Angptl4-/- mice. Angptl4 expression in peritoneal and bone marrow-derived macrophages was highly induced by lipids. Recombinant ANGPTL4 decreased lipid uptake in macrophages, whereas deficiency of ANGPTL4 increased lipid uptake, upregulated lipid-induced genes, and increased respiration. ANGPTL4 deficiency did not alter LPL protein levels in macrophages. Angptl4-hypomorphic mice with partial expression of a truncated N-terminal ANGPTL4 exhibited reduced fasting plasma triglyceride, cholesterol, and non-esterified fatty acid levels, strongly resembling Angptl4-/- mice. However, during high fat feeding, Angptl4-hypomorphic mice showed markedly delayed and attenuated elevation in plasma serum amyloid A and much milder chylous ascites than Angptl4-/- mice, despite similar abundance of lipid-laden giant cells in mesenteric lymph nodes. In conclusion, ANGPTL4 deficiency increases lipid uptake and respiration in macrophages without affecting LPL protein levels. Compared with the absence of ANGPTL4, low levels of N-terminal ANGPTL4 mitigate the development of chylous ascites and an acute-phase response in mice.

2019-08-24 | GSE136240 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data