title: MicroRNA control of podosome formation in vascular smooth muscle cells in vivo and in vitro.
abstract: Smooth muscle cell (SMC) plasticity plays an important role during development and in vascular pathologies such as atherosclerosis and restenosis. It was recently shown that down-regulation of microRNA (miR)-143 and -145, which are coexpressed from a single promoter, regulates the switch from contractile to synthetic phenotype, allowing SMCs to migrate and proliferate. We show in this study that loss of miR-143/145 in vitro and in vivo results in the formation of podosomes, which are actin-rich membrane protrusions involved in the migration of several cell types, including SMCs. We further show that platelet-derived growth factor (PDGF) mediates podosome formation in SMCs through the regulation of miR-143/145 expression via a pathway involving Src and p53. Moreover, we identify key podosome regulators as targets of miR-143 (PDGF receptor alpha and protein kinase C epsilon) and miR-145 (fascin). Thus, dysregulation of the miR-143 and -145 genes is causally involved in the aberrant SMC plasticity encountered during vascular disease, in part through the up-regulation of an autoregulatory loop that promotes podosome formation.
authors.affiliation: Sanford-Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
authors.forename: Manuela
authors.initials: M
authors.lastname: Quintavalle
authors.forename: Leonardo
authors.initials: L
authors.lastname: Elia
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
authors.forename: Sara A
authors.initials: SA
authors.lastname: Courtneidge
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002465:Cell Movement; D022081:Cell Surface Extensions / Q000378:metabolism / Q000648:ultrastructure*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D035683:MicroRNAs; D010982:Platelet-Derived Growth Factor