Suppression of angiopoietin-like 4 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 (Angptl4 iΔEC ), and tr...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-43900-0 |
| _version_ | 1797388199455096832 |
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| author | Balkrishna Chaube Kathryn M. Citrin Mahnaz Sahraei Abhishek K. Singh Diego Saenz de Urturi Wen Ding Richard W. Pierce Raaisa Raaisa Rebecca Cardone Richard Kibbey Carlos Fernández-Hernando Yajaira Suárez |
| author_facet | Balkrishna Chaube Kathryn M. Citrin Mahnaz Sahraei Abhishek K. Singh Diego Saenz de Urturi Wen Ding Richard W. Pierce Raaisa Raaisa Rebecca Cardone Richard Kibbey Carlos Fernández-Hernando Yajaira Suárez |
| author_sort | Balkrishna Chaube |
| collection | DOAJ |
| description | 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 (Angptl4 iΔEC ), 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. |
| first_indexed | 2024-03-08T22:37:18Z |
| format | Article |
| id | doaj.art-6020962f83424a44a099256c33013ee0 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T22:37:18Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-6020962f83424a44a099256c33013ee02023-12-17T12:22:20ZengNature PortfolioNature Communications2041-17232023-12-0114112110.1038/s41467-023-43900-0Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesisBalkrishna Chaube0Kathryn M. Citrin1Mahnaz Sahraei2Abhishek K. Singh3Diego Saenz de Urturi4Wen Ding5Richard W. Pierce6Raaisa Raaisa7Rebecca Cardone8Richard Kibbey9Carlos Fernández-Hernando10Yajaira Suárez11Department of Comparative Medicine, Yale University School of MedicineDepartment of Comparative Medicine, Yale University School of MedicineDepartment of Comparative Medicine, Yale University School of MedicineDepartment of Comparative Medicine, Yale University School of MedicineDepartment of Comparative Medicine, Yale University School of MedicineDepartment of Comparative Medicine, Yale University School of MedicineVascular Biology and Therapeutics Program, Yale University School of MedicineDepartment of Internal Medicine, Yale UniversityDepartment of Internal Medicine, Yale UniversityYale Center for Molecular and System Metabolism, Yale University School of MedicineDepartment of Comparative Medicine, Yale University School of MedicineDepartment of Comparative Medicine, Yale University School of MedicineAbstract 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 (Angptl4 iΔEC ), 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.https://doi.org/10.1038/s41467-023-43900-0 |
| spellingShingle | Balkrishna Chaube Kathryn M. Citrin Mahnaz Sahraei Abhishek K. Singh Diego Saenz de Urturi Wen Ding Richard W. Pierce Raaisa Raaisa Rebecca Cardone Richard Kibbey Carlos Fernández-Hernando Yajaira Suárez Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis Nature Communications |
| title | Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis |
| title_full | Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis |
| title_fullStr | Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis |
| title_full_unstemmed | Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis |
| title_short | Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis |
| title_sort | suppression of angiopoietin like 4 reprograms endothelial cell metabolism and inhibits angiogenesis |
| url | https://doi.org/10.1038/s41467-023-43900-0 |
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