title: Inactivation of the tumour suppressor, PTEN, in smooth muscle promotes a pro-inflammatory phenotype and enhances neointima formation.
abstract: OBJECTIVE
  Phosphatase and tensin homolog (PTEN) is implicated as a negative regulator of vascular smooth muscle cell (SMC) proliferation and injury-induced vascular remodelling. We tested if selective depletion of PTEN only in SMC is sufficient to promote SMC phenotypic modulation, cytokine production, and enhanced neointima formation.
  
  
  RESULTS
  Smooth muscle marker expression and induction of pro-inflammatory cytokines were compared in cultured SMC expressing control or PTEN-specific shRNA. Compared with controls, PTEN-deficient SMC exhibited increased phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signalling and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activity, reduced expression of SM markers (SM-alpha-actin and calponin), and increased production of stromal cell-derived factor-1alpha (SDF-1alpha), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), and chemokine (C-X-C motif) ligand 1 (KC/CXCL1) under basal conditions. PI3K/Akt or mTOR inhibition reversed repression of SM marker expression, whereas PI3K/Akt or NF-kappaB inhibition blocked cytokine induction mediated by PTEN depletion. Carotid ligation in mice with genetic reduction of PTEN specifically in SMC (SMC-specific PTEN heterozygotes) resulted in enhanced neointima formation, increased SMC hyperplasia, reduced SM-alpha-actin and calponin expression, and increased NF-kappaB and cytokine expression compared with wild-types. Lesion formation in SMC-specific heterozygotes was similar to lesion formation in global PTEN heterozygotes, indicating that inactivation of PTEN exclusively in SMC is sufficient to induce considerable increases in neointima formation.
  
  
  CONCLUSIONS
  PTEN activation specifically in SMC is a common upstream regulator of multiple downstream events involved in pathological vascular remodelling, including proliferation, de-differentiation, and production of multiple cytokines.
authors.affiliation: Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Seth B
authors.initials: SB
authors.lastname: Furgeson
authors.forename: Peter A
authors.initials: PA
authors.lastname: Simpson
authors.forename: Insun
authors.initials: I
authors.lastname: Park
authors.forename: Vicki
authors.initials: V
authors.lastname: Vanputten
authors.forename: Henrick
authors.initials: H
authors.lastname: Horita
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Kontos
authors.forename: Raphael A
authors.initials: RA
authors.lastname: Nemenoff
authors.forename: Mary C M
authors.initials: MC
authors.lastname: Weiser-Evans
mesh_terms: D000818:Animals; D020212:Carotid Artery Injuries / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D054337:Cell Dedifferentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D017539:Tunica Intima / Q000201:enzymology* / Q000276:immunology / Q000473:pathology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; C487757:Pten protein, mouse; C487216:Pten protein, rat