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

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.