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

Abstract:

: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.

journal_name

Cell Rep

journal_title

Cell reports

authors

Tan JME,van der Stoel MM,van den Berg M,van Loon NM,Moeton M,Scholl E,van der Wel NN,Kovačević I,Hordijk PL,Loregger A,Huveneers S,Zelcer N

doi

10.1016/j.celrep.2020.107944

subject

Has Abstract

pub_date

2020-08-04 00:00:00

pages

107944

issue

5

issn

2211-1247

pii

S2211-1247(20)30925-6

journal_volume

32

pub_type

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