title: c-Myb Regulates Proliferation and Differentiation of Adventitial Sca1+ Vascular Smooth Muscle Cell Progenitors by Transactivation of Myocardin.
abstract: Vascular smooth muscle cells (VSMCs) are believed to dedifferentiate and proliferate in response to vessel injury. Recently, adventitial progenitor cells were implicated as a source of VSMCs involved in vessel remodeling. c-Myb is a transcription factor known to regulate VSMC proliferation in vivo and differentiation of VSMCs from mouse embryonic stem cell-derived progenitors in vitro. However, the role of c-Myb in regulating specific adult vascular progenitor cell populations was not known. Our objective was to examine the role of c-Myb in the proliferation and differentiation of Sca1(+) adventitial VSMC progenitor cells.
  
  
  
  Using mice with wild-type or hypomorphic c-myb (c-myb(h/h)), BrdU (bromodeoxyuridine) uptake and flow cytometry revealed defective proliferation of Sca1(+) adventitial VSMC progenitor cells at 8, 14, and 28 days post carotid artery denudation injury in c-myb(h/h) arteries. c-myb(h/h) cKit(+)CD34(-)Flk1(-)Sca1(+)CD45(-)Lin(-) cells failed to proliferate, suggesting that c-myb regulates the activation of specific Sca1(+) progenitor cells in vivo and in vitro. Although expression levels of transforming growth factor-β1 did not vary between wild-type and c-myb(h/h) carotid arteries, in vitro differentiation of c-myb(h/h) Sca1(+) cells manifested defective transforming growth factor-β1-induced VSMC differentiation. This is mediated by reduced transcriptional activation of myocardin because chromatin immunoprecipitation revealed c-Myb binding to the myocardin promoter only during differentiation of Sca1(+) cells, myocardin promoter mutagenesis identified 2 specific c-Myb-responsive binding sites, and adenovirus-mediated expression of myocardin rescued the phenotype of c-myb(h/h) progenitors.
  
  
  
  These data support a role for c-Myb in the regulation of VSMC progenitor cells and provide novel insight into how c-myb regulates VSMC differentiation through myocardin.
authors.affiliation: From the Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (E.A.S., M.C., R.B., A.M., O.E.-M., C.S.R., M.H.); and Heart and Stroke Richard Lewar Centre of Excellence, Ted Rogers Centre for Heart Research, McEwen Centre for Regenerative Medicine, and Peter Munk Cardiac Centre (E.A.S., M.C., R.B., C.S.R., M.H.), Department of Laboratory Medicine and Pathobiology (E.A.S., R.B., C.S.R., M.H.), Department of Immunology (C.C.L., C.S.R.), and Department of Medicine (M.C., M.H.), University of Toronto, Ontario, Canada.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Shikatani
authors.affiliation: From the Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (E.A.S., M.C., R.B., A.M., O.E.-M., C.S.R., M.H.); and Heart and Stroke Richard Lewar Centre of Excellence, Ted Rogers Centre for Heart Research, McEwen Centre for Regenerative Medicine, and Peter Munk Cardiac Centre (E.A.S., M.C., R.B., C.S.R., M.H.), Department of Laboratory Medicine and Pathobiology (E.A.S., R.B., C.S.R., M.H.), Department of Immunology (C.C.L., C.S.R.), and Department of Medicine (M.C., M.H.), University of Toronto, Ontario, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Chandy
authors.affiliation: From the Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (E.A.S., M.C., R.B., A.M., O.E.-M., C.S.R., M.H.); and Heart and Stroke Richard Lewar Centre of Excellence, Ted Rogers Centre for Heart Research, McEwen Centre for Regenerative Medicine, and Peter Munk Cardiac Centre (E.A.S., M.C., R.B., C.S.R., M.H.), Department of Laboratory Medicine and Pathobiology (E.A.S., R.B., C.S.R., M.H.), Department of Immunology (C.C.L., C.S.R.), and Department of Medicine (M.C., M.H.), University of Toronto, Ontario, Canada.
authors.forename: Rickvinder
authors.initials: R
authors.lastname: Besla
authors.affiliation: From the Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (E.A.S., M.C., R.B., A.M., O.E.-M., C.S.R., M.H.); and Heart and Stroke Richard Lewar Centre of Excellence, Ted Rogers Centre for Heart Research, McEwen Centre for Regenerative Medicine, and Peter Munk Cardiac Centre (E.A.S., M.C., R.B., C.S.R., M.H.), Department of Laboratory Medicine and Pathobiology (E.A.S., R.B., C.S.R., M.H.), Department of Immunology (C.C.L., C.S.R.), and Department of Medicine (M.C., M.H.), University of Toronto, Ontario, Canada.
authors.forename: Cedric C
authors.initials: CC
authors.lastname: Li
authors.affiliation: From the Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (E.A.S., M.C., R.B., A.M., O.E.-M., C.S.R., M.H.); and Heart and Stroke Richard Lewar Centre of Excellence, Ted Rogers Centre for Heart Research, McEwen Centre for Regenerative Medicine, and Peter Munk Cardiac Centre (E.A.S., M.C., R.B., C.S.R., M.H.), Department of Laboratory Medicine and Pathobiology (E.A.S., R.B., C.S.R., M.H.), Department of Immunology (C.C.L., C.S.R.), and Department of Medicine (M.C., M.H.), University of Toronto, Ontario, Canada.
authors.forename: Abdul
authors.initials: A
authors.lastname: Momen
authors.affiliation: From the Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (E.A.S., M.C., R.B., A.M., O.E.-M., C.S.R., M.H.); and Heart and Stroke Richard Lewar Centre of Excellence, Ted Rogers Centre for Heart Research, McEwen Centre for Regenerative Medicine, and Peter Munk Cardiac Centre (E.A.S., M.C., R.B., C.S.R., M.H.), Department of Laboratory Medicine and Pathobiology (E.A.S., R.B., C.S.R., M.H.), Department of Immunology (C.C.L., C.S.R.), and Department of Medicine (M.C., M.H.), University of Toronto, Ontario, Canada.
authors.forename: Omar
authors.initials: O
authors.lastname: El-Mounayri
authors.affiliation: From the Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (E.A.S., M.C., R.B., A.M., O.E.-M., C.S.R., M.H.); and Heart and Stroke Richard Lewar Centre of Excellence, Ted Rogers Centre for Heart Research, McEwen Centre for Regenerative Medicine, and Peter Munk Cardiac Centre (E.A.S., M.C., R.B., C.S.R., M.H.), Department of Laboratory Medicine and Pathobiology (E.A.S., R.B., C.S.R., M.H.), Department of Immunology (C.C.L., C.S.R.), and Department of Medicine (M.C., M.H.), University of Toronto, Ontario, Canada.
authors.forename: Clinton S
authors.initials: CS
authors.lastname: Robbins
authors.affiliation: From the Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (E.A.S., M.C., R.B., A.M., O.E.-M., C.S.R., M.H.); and Heart and Stroke Richard Lewar Centre of Excellence, Ted Rogers Centre for Heart Research, McEwen Centre for Regenerative Medicine, and Peter Munk Cardiac Centre (E.A.S., M.C., R.B., C.S.R., M.H.), Department of Laboratory Medicine and Pathobiology (E.A.S., R.B., C.S.R., M.H.), Department of Immunology (C.C.L., C.S.R.), and Department of Medicine (M.C., M.H.), University of Toronto, Ontario, Canada. mansoor.husain@utoronto.ca.
authors.forename: Mansoor
authors.initials: M
authors.lastname: Husain
mesh_terms: D063194:Adventitia / Q000187:drug effects / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000067696:Ataxin-1 / Q000378:metabolism*; D001665:Binding Sites; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D066253:Vascular Remodeling; D000099251:Myocardin
chemical_list: D000067696:Ataxin-1; D009687:Nuclear Proteins; D020598:Proto-Oncogene Proteins c-myb; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1; D000099251:Myocardin; C000593750:Atxn1 protein, mouse
keywords: c-Myb genes; cell differentiation; myocardin; progenitor cells; smooth muscle cells