2. Academic Validation
  3. The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting

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

  • Cell Rep. 2020 Aug 4;32(5):107944. doi: 10.1016/j.celrep.2020.107944.
Josephine Mathilde Elisabeth Tan 1,  Miesje Maxime van der Stoel 1,  Marlene van den Berg 1,  Nienke Marlies van Loon 1,  Martina Moeton 1,  Edwin Scholl 2,  Nicole Neeltje van der Wel 2,  Igor Kovačević 3,  Peter Lodewijk Hordijk 4,  Anke Loregger 1,  Stephan Huveneers 5,  Noam Zelcer 6
Affiliations

Affiliations

  • 1 Department of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
  • 2 Department of Medical Biology, Electron Microscopy Center Amsterdam, Amsterdam UMC, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
  • 3 Department 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, Germany.
  • 4 Department of Physiology, Amsterdam University Medical Centers, location VUmc, Amsterdam, the Netherlands.
  • 5 Department of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands. Electronic address: s.huveneers@amsterdamumc.nl.
  • 6 Department of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands. Electronic address: n.zelcer@amsterdamumc.nl.
PMID: 32755570 DOI: 10.1016/j.celrep.2020.107944
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.

Keywords

MARCH6; MARCHF6; SQLE; VE-cadherin; adherens junction; angiogenesis; cholesterol metabolism; endothelial barrier; membrane organization; post-transcriptional regulation.

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