The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting
Summary: The endothelial monolayer forms a barrier between the lumen of blood vessels and the underlying tissues. Stable VE-cadherin-based adherens junctions are essential for maintaining this barrier, whereas their remodeling is required for angiogenesis in health and disease. Here, we position the...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-08-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720309256 |
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| author | Josephine Mathilde Elisabeth Tan Miesje Maxime van der Stoel Marlene van den Berg Nienke Marlies van Loon Martina Moeton Edwin Scholl Nicole Neeltje van der Wel Igor Kovačević Peter Lodewijk Hordijk Anke Loregger Stephan Huveneers Noam Zelcer |
| author_facet | Josephine Mathilde Elisabeth Tan Miesje Maxime van der Stoel Marlene van den Berg Nienke Marlies van Loon Martina Moeton Edwin Scholl Nicole Neeltje van der Wel Igor Kovačević Peter Lodewijk Hordijk Anke Loregger Stephan Huveneers Noam Zelcer |
| author_sort | Josephine Mathilde Elisabeth Tan |
| collection | DOAJ |
| description | Summary: The endothelial monolayer forms a barrier between the lumen of blood vessels and the underlying tissues. Stable VE-cadherin-based adherens junctions are essential for maintaining this barrier, whereas their remodeling is required for angiogenesis in health and disease. Here, we position the ERAD-associated ubiquitin ligase MARCH6 as a determinant of angiogenic sprouting and barrier integrity through its ability to promote the degradation of the rate-limiting cholesterol biosynthetic enzyme squalene epoxidase (SQLE). Accordingly, MARCHF6 ablation in endothelial cells increases SQLE protein and cholesterol load. This leads to altered membrane order, disorganized adherens junctions, decreased endothelial barrier function, and impaired SQLE-dependent sprouting angiogenesis. Akin to MARCHF6 silencing, the overexpression of SQLE impairs angiogenesis. However, angiogenesis is also attenuated when SQLE is silenced, indicating that fine-tuning cholesterol biosynthesis is a determinant of healthy endothelial function. In summary, we propose a mechanistic link between regulation of cholesterol homeostasis by the MARCH6-SQLE axis and endothelial integrity and angiogenesis. |
| first_indexed | 2024-12-12T23:35:19Z |
| format | Article |
| id | doaj.art-d956f3cfee4f47078c64a2d549743b71 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-12T23:35:19Z |
| publishDate | 2020-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-d956f3cfee4f47078c64a2d549743b712022-12-22T00:07:32ZengElsevierCell Reports2211-12472020-08-01325107944The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic SproutingJosephine Mathilde Elisabeth Tan0Miesje Maxime van der Stoel1Marlene van den Berg2Nienke Marlies van Loon3Martina Moeton4Edwin Scholl5Nicole Neeltje van der Wel6Igor Kovačević7Peter Lodewijk Hordijk8Anke Loregger9Stephan Huveneers10Noam Zelcer11Department of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the NetherlandsDepartment of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the NetherlandsDepartment of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the NetherlandsDepartment of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the NetherlandsDepartment of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the NetherlandsDepartment of Medical Biology, Electron Microscopy Center Amsterdam, Amsterdam UMC, Meibergdreef 9, 1105AZ Amsterdam, the NetherlandsDepartment of Medical Biology, Electron Microscopy Center Amsterdam, Amsterdam UMC, Meibergdreef 9, 1105AZ Amsterdam, the NetherlandsDepartment of Physiology, Amsterdam University Medical Centers, location VUmc, Amsterdam, the Netherlands; Institute for Physiological Chemistry, Medical Faculty, Martin Luther University Halle-Wittenberg, Hollystrasse 1, 06114 Halle, GermanyDepartment of Physiology, Amsterdam University Medical Centers, location VUmc, Amsterdam, the NetherlandsDepartment of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the NetherlandsDepartment of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Corresponding authorDepartment of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Corresponding authorSummary: The endothelial monolayer forms a barrier between the lumen of blood vessels and the underlying tissues. Stable VE-cadherin-based adherens junctions are essential for maintaining this barrier, whereas their remodeling is required for angiogenesis in health and disease. Here, we position the ERAD-associated ubiquitin ligase MARCH6 as a determinant of angiogenic sprouting and barrier integrity through its ability to promote the degradation of the rate-limiting cholesterol biosynthetic enzyme squalene epoxidase (SQLE). Accordingly, MARCHF6 ablation in endothelial cells increases SQLE protein and cholesterol load. This leads to altered membrane order, disorganized adherens junctions, decreased endothelial barrier function, and impaired SQLE-dependent sprouting angiogenesis. Akin to MARCHF6 silencing, the overexpression of SQLE impairs angiogenesis. However, angiogenesis is also attenuated when SQLE is silenced, indicating that fine-tuning cholesterol biosynthesis is a determinant of healthy endothelial function. In summary, we propose a mechanistic link between regulation of cholesterol homeostasis by the MARCH6-SQLE axis and endothelial integrity and angiogenesis.http://www.sciencedirect.com/science/article/pii/S2211124720309256VE-cadherincholesterol metabolismendothelial barrierSQLEMARCH6MARCHF6 |
| spellingShingle | Josephine Mathilde Elisabeth Tan Miesje Maxime van der Stoel Marlene van den Berg Nienke Marlies van Loon Martina Moeton Edwin Scholl Nicole Neeltje van der Wel Igor Kovačević Peter Lodewijk Hordijk Anke Loregger Stephan Huveneers Noam Zelcer The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting Cell Reports VE-cadherin cholesterol metabolism endothelial barrier SQLE MARCH6 MARCHF6 |
| title | The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting |
| title_full | The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting |
| title_fullStr | The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting |
| title_full_unstemmed | The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting |
| title_short | The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting |
| title_sort | march6 sqle axis controls endothelial cholesterol homeostasis and angiogenic sprouting |
| topic | VE-cadherin cholesterol metabolism endothelial barrier SQLE MARCH6 MARCHF6 |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720309256 |
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