The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting

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-ass...

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Published in:	Cell reports (Cambridge) Vol. 32; no. 5; p. 107944
Main Authors:	Tan, Josephine Mathilde Elisabeth, van der Stoel, Miesje Maxime, van den Berg, Marlene, van Loon, Nienke Marlies, Moeton, Martina, Scholl, Edwin, van der Wel, Nicole Neeltje, Kovačević, Igor, Hordijk, Peter Lodewijk, Loregger, Anke, Huveneers, Stephan, Zelcer, Noam
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 04-08-2020 Elsevier
Subjects:	adherens junction Adherens Junctions - metabolism Adherens Junctions - ultrastructure angiogenesis Antigens, CD - metabolism Cadherins - metabolism Cholesterol - metabolism endothelial barrier Gene Silencing HEK293 Cells Homeostasis Human Umbilical Vein Endothelial Cells - metabolism Human Umbilical Vein Endothelial Cells - ultrastructure Humans MARCH6 MARCHF6 membrane organization Membrane Proteins - metabolism Neovascularization, Physiologic post-transcriptional regulation SQLE Squalene Monooxygenase - metabolism Ubiquitin-Protein Ligases - metabolism VE-cadherin SQLE adherens junction cholesterol metabolism angiogenesis membrane organization post-transcriptional regulation VE-cadherin endothelial barrier MARCH6 MARCHF6
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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. [Display omitted] •Regulation of cholesterol synthesis is a determinant of endothelial function•MARCH6 governs endothelial cholesterol homeostasis by promoting degradation of SQLE•MARCH6 loss impairs VE-cadherin-based adherens junctions and sprouting angiogenesis•Angiogenesis is dependent on fine-tuning SQLE levels in endothelial cells Tan et al. identify the E3-ligase MARCH6 as an important regulator of endothelial sprouting angiogenesis, owing to its ability to degrade the cholesterol biosynthetic enzyme SQLE. The study highlights that adequate SQLE levels are a critical determinant of maintaining endothelial junctions and proper sprouting angiogenesis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2020.107944