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A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors
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A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors

Published on: March 15, 2016

Myoferlin regulates vascular endothelial growth factor receptor-2 stability and function

Pascal N Bernatchez1, Lisette Acevedo, Carlos Fernandez-Hernando

  • 1Department of Pharmacology and Vascular Biology & Transplantation Program, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06536, USA.

The Journal of Biological Chemistry
|August 19, 2007
PubMed

Insights

Myoferlin, a protein previously linked to muscle disorders, is crucial for blood vessel function. Its absence impairs vascular endothelial growth factor signaling, affecting cell growth, migration, and nitric oxide release.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Vascular Biology

Background:

  • Myoferlin and dysferlin are ferlin family membrane proteins implicated in muscular dystrophy phenotypes due to impaired plasma membrane integrity.
  • The biological functions of myoferlin in non-muscle tissues, particularly endothelial cells, were previously unknown.

Purpose of the Study:

  • To investigate the role of myoferlin in endothelial cells and vascular tissues.
  • To elucidate the molecular mechanisms by which myoferlin influences vascular endothelial growth factor (VEGF) signaling.

Main Methods:

  • Proteomic analysis of endothelial cell (EC) caveolae/lipid raft microdomains to identify myoferlin.
  • Assessment of EC proliferation, migration, and nitric oxide (NO) release in myoferlin-deficient models.
  • Western blotting and surface biotinylation to analyze VEGF receptor-2 (VEGFR-2) expression and phosphorylation.
  • In vivo studies using myoferlin-deficient mice.
  • Co-immunoprecipitation to identify protein interactions.

Main Results:

  • Myoferlin is highly expressed in ECs and vascular tissues, localizing to caveolae/lipid raft microdomains.
  • Loss of myoferlin impairs EC proliferation, migration, and VEGF-induced nitric oxide (NO) release.
  • Myoferlin deficiency reduces VEGFR-2 expression and autophosphorylation, while its presence enhances VEGFR-2 membrane expression and signaling.
  • Myoferlin interacts with dynamin-2 and VEGFR-2, preventing CBL-dependent VEGFR-2 degradation.
  • VEGFR-2 levels and VEGF-induced permeability are impaired in myoferlin-deficient mice.

Conclusions:

  • Myoferlin plays a novel and critical role in regulating endothelial cell function and vascular integrity.
  • Myoferlin is essential for proper VEGF signaling by stabilizing VEGFR-2 and preventing its proteasomal degradation.
  • These findings reveal a new link between membrane integrity and VEGF signaling pathways in the vasculature.

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