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Fbxw7 controls angiogenesis by regulating endothelial Notch activity

Nanae Izumi1, Christian Helker, Manuel Ehling

  • 1Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, Muenster, Germany.

Plos One
|August 1, 2012
PubMed

Insights

Fbxw7 is crucial for blood vessel growth by degrading Notch. Loss of Fbxw7 impairs angiogenesis, increasing Notch activity and hindering vessel development in mice and zebrafish.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Vascular Biology

Background:

  • Notch signaling is essential for blood vessel formation, regulating tip cell selection, proliferation, and differentiation.
  • Fbxw7, an E3 ubiquitin ligase, targets proteins like Notch for degradation, influencing cellular processes.

Purpose of the Study:

  • To investigate the role of Fbxw7 in angiogenesis and its regulation of Notch signaling in endothelial cells.
  • To determine if Fbxw7 acts as a positive or negative regulator of blood vessel growth.

Main Methods:

  • Utilized inducible and endothelial cell-specific Fbxw7 knockout mice (Fbxw7(iECKO)) to study retinal angiogenesis.
  • Employed siRNA knockdown of Fbxw7 in human endothelial cells and morpholino injection in zebrafish embryos.
  • Assessed Notch pathway activity, Dll4 expression, and intersegmental vessel (ISV) sprouting.

Main Results:

  • Fbxw7 deficiency in mice led to impaired retinal blood vessel growth and increased Dll4 expression.
  • Fbxw7 knockdown in human endothelial cells stabilized the active Notch intracellular domain.
  • Fbxw7 inhibition in zebrafish embryos disrupted ISV sprouting, a phenotype reversed by Notch pathway inactivation.

Conclusions:

  • Fbxw7 is a critical positive regulator of angiogenesis, acting by promoting the degradation of active Notch in endothelial cells.
  • The Fbxw7-Notch axis is a key determinant of vascular development and integrity.
  • Targeting Fbxw7 may offer therapeutic strategies for modulating angiogenesis.

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