A new role for the muscle repair protein dysferlin in endothelial cell adhesion and angiogenesis.
OBJECTIVE
Ferlins are known to regulate plasma membrane repair in muscle cells and are linked to muscular dystrophy and cardiomyopathy. Recently, using proteomic analysis of caveolae/lipid rafts, we reported that endothelial cells (EC) express myoferlin and that it regulates membrane expression of vascular endothelial growth factor receptor 2 (VEGFR-2). The goal of this study was to document the presence of other ferlins in EC.


RESULTS
EC expressed another ferlin, dysferlin, and that in contrast to myoferlin, it did not regulate VEGFR-2 expression levels or downstream signaling (nitric oxide and Erk1/2 phosphorylation). Instead, loss of dysferlin in subconfluent EC resulted in deficient adhesion followed by growth arrest, an effect not observed in confluent EC. In vivo, dysferlin was also detected in intact and diseased blood vessels of rodent and human origin, and angiogenic challenge of dysferlin-null mice resulted in impaired angiogenic response compared with control mice. Mechanistically, loss of dysferlin in cultured EC caused polyubiquitination and proteasomal degradation of platelet endothelial cellular adhesion molecule-1 (PECAM-1/CD31), an adhesion molecule essential for angiogenesis. In addition, adenovirus-mediated gene transfer of PECAM-1 rescued the abnormal adhesion of EC caused by dysferlin gene silencing.


CONCLUSIONS
Our data describe a novel pathway for PECAM-1 regulation and broaden the functional scope of ferlins in angiogenesis and specialized ferlin-selective protein cargo trafficking in vascular settings.
Sharma
Arpeeta
A
Providence Heart and Lung Institute, St. Paul's Hospital, University of British Columbia, Vancouver V6Z 1Y6, British Columbia, Canada.
Yu
Carol
C
Leung
Cleo
C
Trane
Andy
A
Lau
Marco
M
Utokaparch
Soraya
S
Shaheen
Furquan
F
Sheibani
Nader
N
Bernatchez
Pascal
P
D000818:Animals; D002417:Cattle; D002448:Cell Adhesion / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation; D000073939:Dysferlin; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D009124:Muscle Proteins / Q000096:biosynthesis / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology
C114839:DYSF protein, human; C497505:Dysf protein, mouse; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D040301:Vascular Endothelial Growth Factor Receptor-2