title: Caveolin-1 is required for contractile phenotype expression by airway smooth muscle cells.
abstract: Airway smooth muscle cells exhibit phenotype plasticity that underpins their ability to contribute both to acute bronchospasm and to the features of airway remodelling in chronic asthma. A feature of mature, contractile smooth muscle cells is the presence of abundant caveolae, plasma membrane invaginations that develop from the association of lipid rafts with caveolin-1, but the functional role of caveolae and caveolin-1 in smooth muscle phenotype plasticity is unknown. Here, we report a key role for caveolin-1 in promoting phenotype maturation of differentiated airway smooth muscle induced by transforming growth factor (TGF)-β(1). As assessed by Western analysis and laser scanning cytometry, caveolin-1 protein expression was selectively enriched in contractile phenotype airway myocytes. Treatment with TGF-β(1) induced profound increases in the contractile phenotype markers sm-α-actin and calponin in cells that also accumulated abundant caveolin-1; however, siRNA or shRNAi inhibition of caveolin-1 expression largely prevented the induction of these contractile phenotype marker proteins by TGF-β(1). The failure by TGF-β(1) to adequately induce the expression of these smooth muscle specific proteins was accompanied by a strongly impaired induction of eukaryotic initiation factor-4E binding protein(4E-BP)1 phosphorylation with caveolin-1 knockdown, indicating that caveolin-1 expression promotes TGF-β(1) signalling associated with myocyte maturation and hypertrophy. Furthermore, we observed increased expression of caveolin-1 within the airway smooth muscle bundle of guinea pigs repeatedly challenged with allergen, which was associated with increased contractile protein expression, thus providing in vivo evidence linking caveolin-1 expression with accumulation of contractile phenotype myocytes. Collectively, we identify a new function for caveolin-1 in controlling smooth muscle phenotype; this mechanism could contribute to allergic asthma.
authors.affiliation: Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Reinoud
authors.initials: R
authors.lastname: Gosens
authors.forename: Gerald L
authors.initials: GL
authors.lastname: Stelmack
authors.forename: Sophie T
authors.initials: ST
authors.lastname: Bos
authors.forename: Gordon
authors.initials: G
authors.lastname: Dueck
authors.forename: Mark M
authors.initials: MM
authors.lastname: Mutawe
authors.forename: Dedmer
authors.initials: D
authors.lastname: Schaafsma
authors.forename: Helmut
authors.initials: H
authors.lastname: Unruh
authors.forename: William T
authors.initials: WT
authors.lastname: Gerthoffer
authors.forename: Johan
authors.initials: J
authors.lastname: Zaagsma
authors.forename: Herman
authors.initials: H
authors.lastname: Meurs
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
mesh_terms: D000199:Actins / Q000096:biosynthesis; D056151:Airway Remodeling; D000818:Animals; D001249:Asthma / Q000503:physiopathology; D002135:Calcium-Binding Proteins; D021941:Caveolae / Q000378:metabolism / Q000502:physiology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004285:Dogs; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D008840:Microfilament Proteins; D032342:Muscle Cells; D009119:Muscle Contraction; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000502:physiology; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering; D012137:Respiratory System / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology; D000096985:Calponins
chemical_list: D000199:Actins; D002135:Calcium-Binding Proteins; D051242:Caveolin 1; D039561:Eukaryotic Initiation Factor-4E; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D000096985:Calponins