A new role for the muscle repair protein dysferlin in endothelial cell adhesion and angiogenesis.

Publications // Sheibani Lab // Nov 01 2010

PubMed ID: 20724702

Author(s): Sharma A, Yu C, Leung C, Trane A, Lau M, Utokaparch S, Shaheen F, Sheibani N, Bernatchez P. A new role for the muscle repair protein dysferlin in endothelial cell adhesion and angiogenesis. Arterioscler Thromb Vasc Biol. 2010 Nov;30(11):2196-204. doi: 10.1161/ATVBAHA.110.208108. Epub 2010 Aug 19. PMID 20724702

Journal: Arteriosclerosis, Thrombosis, And Vascular Biology, Volume 30, Issue 11, Nov 2010

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.

METHODS AND 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.