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Suppression of ANGPTL4 Reprograms Endothelial Cell Metabolism and Inhibits Angiogenesis

ABSTRACT: Suppression of ANGPTL4 Reprograms Endothelial Cell Metabolism and Inhibits Angiogenesis

PROVIDER: PRJNA869060 | ENA |

REPOSITORIES: ENA

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Suppression of ANGPTL4 Reprograms Endothelial Cell Metabolism and Inhibits Angiogenesis

Project description: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.

2023-11-22 | GSE211128 | GEO

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

Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis.

Project description: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 (Angptl4iΔEC), 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.

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Apigenin inhibits tumor angiogenesis by suppressing microvesicle biogenesis

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COCO/DAND5 inhibits developmental and pathological ocular angiogenesis

Project description:COCO/DAND5 inhibits developmental and pathological ocular angiogenesis

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

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COCO/DAND5 inhibits developmental and pathological ocular angiogenesis

Project description:Neovascularization contributes to multiple visual disorders including age-related macular degeneration (AMD). Current therapies for treating ocular angiogenesis are centered on the inhibition of vascular endothelial growth factor (VEGF). While clinically effective, some AMD patients are refractory or develop resistance to anti-VEGF and concerns of increased risks of developing geographic atrophy following long-term treatment have been raised. Identification of alternative pathways to inhibit pathological angiogenesis is thus important. We have identified a novel inhibitor of angiogenesis, COCO/DAND5, a member of the Cerberus-related DAN family. We demonstrate that COCO inhibits sprouting, migration and cellular proliferation of cultured endothelial cells. Intravitreal injections of COCO inhibited retinal vascularization during development and in models of retinopathy of prematurity and AMD. COCO equally abrogated angiogenesis in choroid explants and in a model of choroidal neovascularization. Mechanistically, COCO inhibited the expression of TGFβ and BMP pathwaysand altered ATP production, glucose uptake and redox balance of endothelial cells. Together, these data show that COCO is an inhibitor of retinal and choroidal angiogenesis, possibly representing a therapeutic option for the treatment of neovascular ocular diseases.

2020-12-22 | GSE160099 | GEO

Apigenin inhibits tumor angiogenesis by suppressing microvesicle biogenesis

Project description:Apigenin regulates multiple pathways related to microvesicle biogenesis without affecting the expression of small Rho GTPase activator guanine nucleotide exchange factors (GEFs). However, apigenin can primarily targets ARHGEF1 protein, a GEF of the small GTPases, thereby inhibiting the activity of small G proteins such as Cdc42, which is essential in regulating the signaling for the release of microvesicles from tumor cells. Targeting ARHGEF1, apigenin effectively prevents tumor cells from releasing microvesicles. This, in turn, inhibits tumor angiogenesis related to VEGF90K transport on microvesicles, ultimately impeding tumor progression.

2024-07-22 | GSE251817 | GEO

Comparative expression data between ANGPTL4+/+ and ANGPTL4-/- mice whole colon tissue during DSS or SA-induced inflammation.

Project description:Protracted inflammatory responses are signatures common to many gastrointestinal disorders. Severe and chronic disorders often bring about extensive tissue damage, in turn leading to hypercytokinemia. Here, we show that stimuli like dextran sulphate sodium salt (DSS) and stearic acid (SA) cause acute colonic inflammation, and ANGPTL4 is an important regulator in mediating the extent of colonic inflammation. Using comparative microarray gene expression analysis, we seek to identify genes whose expression are altered during inflammation between ANGPTL4+/+ and ANGPTL4-/- mice.

2017-03-28 | GSE78500 | GEO

ZNF354C is a transcriptional repressor that inhibits angiogenesis in endothelial cells

Project description:ZNF354C is a transcriptional repressor that inhibits angiogenesis in endothelial cells

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