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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.
Pubmed ID: 32755570
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Cell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis recombinant polyclonal secondary targets IgG (H+L)
View all literature mentionsThis polyclonal targets VE-Cadherin
View all literature mentionsThis monoclonal targets CD144 (VE-Cadherin)
View all literature mentionsThis recombinant polyclonal secondary targets IgG (Heavy Chain)
View all literature mentionsThis monoclonal targets GM130
View all literature mentionsThis monoclonal targets V5 Tag
View all literature mentionsThis monoclonal targets actin
View all literature mentionsThis monoclonal targets Human VE-cadherin
View all literature mentionsCell line HEK293T/17 is a Transformed cell line with a species of origin Homo sapiens (Human)
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