title: SDF-1α induction in mature smooth muscle cells by inactivation of PTEN is a critical mediator of exacerbated injury-induced neointima formation.
abstract: OBJECTIVE
  PTEN inactivation selectively in smooth muscle cells (SMC) initiates multiple downstream events driving neointima formation, including SMC cytokine/chemokine production, in particular stromal cell-derived factor-1α (SDF-1α). We investigated the effects of SDF-1α on resident SMC and bone marrow-derived cells and in mediating neointima formation.
  
  
  RESULTS
  Inducible, SMC-specific PTEN knockout mice (PTEN iKO) were bred to floxed-stop ROSA26-β-galactosidase (βGal) mice to fate-map mature SMC in response to injury; mice received wild-type green fluorescent protein-labeled bone marrow to track recruitment. Following wire-induced femoral artery injury, βGal(+) SMC accumulated in the intima and adventitia. Compared with wild-type, PTEN iKO mice exhibited massive neointima formation, increased replicating intimal and medial βGal(+)SMC, and enhanced vascular recruitment of bone marrow cells following injury. Inhibiting SDF-1α blocked these events and reversed enhanced neointima formation observed in PTEN iKO mice. Most recruited green fluorescent protein(+) cells stained positive for macrophage markers but not SMC markers. SMC-macrophage interactions resulted in a persistent SMC inflammatory phenotype that was dependent on SMC PTEN and SDF-1α expression.
  
  
  CONCLUSIONS
  Resident SMC play a multifaceted role in neointima formation by contributing the majority of neointimal cells, regulating recruitment of inflammatory cells, and contributing to adventitial remodeling. The SMC PTEN-SDF-1α axis is a critical regulator of these events.
authors.affiliation: Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Raphael A
authors.initials: RA
authors.lastname: Nemenoff
authors.forename: Henrick
authors.initials: H
authors.lastname: Horita
authors.forename: Allison C
authors.initials: AC
authors.lastname: Ostriker
authors.forename: Seth B
authors.initials: SB
authors.lastname: Furgeson
authors.forename: Peter A
authors.initials: PA
authors.lastname: Simpson
authors.forename: Vicki
authors.initials: V
authors.lastname: VanPutten
authors.forename: Joseph
authors.initials: J
authors.lastname: Crossno
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Mary C M
authors.initials: MC
authors.lastname: Weiser-Evans
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology*; D058426:Neointima / Q000209:etiology*; D051059:PTEN Phosphohydrolase / Q000502:physiology*
chemical_list: D054377:Chemokine CXCL12; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse