title: Myoferlin gene silencing decreases Tie-2 expression in vitro and angiogenesis in vivo.
abstract: Angiogenesis consists in the growth of new blood vessels from pre-existing ones. Although anti-angiogenesis interventions have been shown to have therapeutic properties in human diseases such as cancer, their effect is only partial and the identification of novel modulators of angiogenesis is warranted. Recently, we reported the unexpected proteomic identification in endothelial cells (EC) of Myoferlin, a member of the Ferlin family of transmembrane proteins. Ferlins are well known to regulate the fusion of lipid vesicles at the plasma membrane in muscle cells, and we showed that Myoferlin gene knockdown not only decreases lipid vesicle fusion in EC but also attenuates Vascular Endothelial Growth Factor (VEGF) Receptor-2 (VEGFR-2) expression. Herein, we show that Myoferlin gene silencing in cultured EC also results in attenuated expression of a second tyrosine kinase receptor, Tie-2, which is another well-described angiogenic receptor. Most importantly, we provide evidence that delivery of a low-volume Myoferlin siRNA preparation in mouse tissues results in attenuated angiogenesis and edema formation. This provides the first evidence that acute Myoferlin knockdown has anti-angiogenic effects and validates Myoferlin as an anti-angiogenesis target. Furthermore, this supports the unexpected but increasingly accepted concept that proper tyrosine kinase receptors expression at the plasma membrane requires Myoferlin.
authors.affiliation: The Providence Heart and Lung Institute, The James Hogg Research Centre, St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Carol
authors.initials: C
authors.lastname: Yu
authors.forename: Arpeeta
authors.initials: A
authors.lastname: Sharma
authors.forename: Andy
authors.initials: A
authors.lastname: Trane
authors.forename: Soraya
authors.initials: S
authors.lastname: Utokaparch
authors.forename: Cleo
authors.initials: C
authors.lastname: Leung
authors.forename: Pascal
authors.initials: P
authors.lastname: Bernatchez
mesh_terms: D000818:Animals; D002417:Cattle; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D020868:Gene Silencing; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics*; D018919:Neovascularization, Physiologic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000096:biosynthesis* / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C521810:myoferlin protein, mouse; C467480:vascular endothelial growth factor A, mouse; D050721:Proto-Oncogene Proteins c-cbl; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; D046988:Proteasome Endopeptidase Complex; C493849:Cbl protein, mouse