title: Wnt2 and WISP-1/CCN4 Induce Intimal Thickening via Promotion of Smooth Muscle Cell Migration.
abstract: Increased vascular smooth muscle cell (VSMC) migration leads to intimal thickening which acts as a soil for atherosclersosis, as well as causing coronary artery restenosis after stenting and vein graft failure. Investigating factors involved in VSMC migration may enable us to reduce intimal thickening and improve patient outcomes. In this study, we determined whether Wnt proteins regulate VSMC migration and thereby intimal thickening.
  
  
  
  Wnt2 mRNA and protein expression were specifically increased in migrating mouse aortic VSMCs. Moreover, VSMC migration was induced by recombinant Wnt2 in vitro. Addition of recombinant Wnt2 protein increased Wnt1-inducible signaling pathway protein-1 (WISP-1) mRNA by ≈1.7-fold, via β-catenin/T-cell factor signaling, whereas silencing RNA knockdown of Wnt-2 reduced WISP-1 mRNA by ≈65%. Treatment with rWISP-1 significantly increased VSMC migration by ≈1.5-fold, whereas WISP-1 silencing RNA knockdown reduced migration by ≈40%. Wnt2 and WISP-1 effects were integrin-dependent and not additive, indicating that Wnt2 promoted VSMC migration via WISP-1. Additionally, Wnt2 and WISP-1 were significantly increased and colocated in human coronary arteries with intimal thickening. Reduced Wnt2 and WISP-1 levels in mouse carotid arteries from Wnt2(+/-) and WISP-1(-/-) mice, respectively, significantly suppressed intimal thickening in response to carotid artery ligation. In contrast, elevation of plasma WISP-1 via an adenovirus encoding WISP-1 significantly increased intimal thickening by ≈1.5-fold compared with mice receiving control virus.
  
  
  
  Upregulation of Wnt2 expression enhanced WISP-1 and promoted VSMC migration and thereby intimal thickening. As novel regulators of VSMC migration and intimal thickening, Wnt2 or WISP-1 may provide a potential therapy for restenosis and vein graft failure.
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Williams
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Carina A E
authors.initials: CA
authors.lastname: Mill
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Bethan A
authors.initials: BA
authors.lastname: Monk
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hulin-Curtis
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Johnson
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol, UK. s.j.george@bristol.ac.uk.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: George
mesh_terms: D000818:Animals; D055511:CCN Intercellular Signaling Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005838:Genotype; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058426:Neointima; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D034622:RNA Interference; D011994:Recombinant Proteins / Q000494:pharmacology; D051820:TCF Transcription Factors / Q000378:metabolism; D014162:Transfection; D060449:Wnt Signaling Pathway; D051154:Wnt2 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; C492067:CCN4 protein, mouse; C495267:CTNNB1 protein, mouse; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D051820:TCF Transcription Factors; C495244:WNT2 protein, human; D051154:Wnt2 Protein; D051176:beta Catenin
keywords: WISP-1/CCN4; Wnt2; intimal thickening; restenosis; smooth muscle cell migration