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Inactivation of the tumour suppressor, PTEN, in smooth muscle promotes a pro-inflammatory phenotype and enhances neointima formation.

Publication ,  Journal Article
Furgeson, SB; Simpson, PA; Park, I; Vanputten, V; Horita, H; Kontos, CD; Nemenoff, RA; Weiser-Evans, MCM
Published in: Cardiovasc Res
May 1, 2010

AIMS: 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. METHODS AND 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. CONCLUSION: 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.

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Published In

Cardiovasc Res

DOI

EISSN

1755-3245

Publication Date

May 1, 2010

Volume

86

Issue

2

Start / End Page

274 / 282

Location

England

Related Subject Headings

  • Tunica Intima
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • Rats
  • RNA Interference
  • Proto-Oncogene Proteins c-akt
  • Protein Serine-Threonine Kinases
  • Phosphatidylinositol 3-Kinases
  • Phenotype
  • PTEN Phosphohydrolase
 

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Furgeson, S. B., Simpson, P. A., Park, I., Vanputten, V., Horita, H., Kontos, C. D., … Weiser-Evans, M. C. M. (2010). Inactivation of the tumour suppressor, PTEN, in smooth muscle promotes a pro-inflammatory phenotype and enhances neointima formation. Cardiovasc Res, 86(2), 274–282. https://doi.org/10.1093/cvr/cvp425
Furgeson, Seth B., Peter A. Simpson, Insun Park, Vicki Vanputten, Henrick Horita, Christopher D. Kontos, Raphael A. Nemenoff, and Mary C. M. Weiser-Evans. “Inactivation of the tumour suppressor, PTEN, in smooth muscle promotes a pro-inflammatory phenotype and enhances neointima formation.Cardiovasc Res 86, no. 2 (May 1, 2010): 274–82. https://doi.org/10.1093/cvr/cvp425.
Furgeson SB, Simpson PA, Park I, Vanputten V, Horita H, Kontos CD, et al. Inactivation of the tumour suppressor, PTEN, in smooth muscle promotes a pro-inflammatory phenotype and enhances neointima formation. Cardiovasc Res. 2010 May 1;86(2):274–82.
Furgeson, Seth B., et al. “Inactivation of the tumour suppressor, PTEN, in smooth muscle promotes a pro-inflammatory phenotype and enhances neointima formation.Cardiovasc Res, vol. 86, no. 2, May 2010, pp. 274–82. Pubmed, doi:10.1093/cvr/cvp425.
Furgeson SB, Simpson PA, Park I, Vanputten V, Horita H, Kontos CD, Nemenoff RA, Weiser-Evans MCM. Inactivation of the tumour suppressor, PTEN, in smooth muscle promotes a pro-inflammatory phenotype and enhances neointima formation. Cardiovasc Res. 2010 May 1;86(2):274–282.
Journal cover image

Published In

Cardiovasc Res

DOI

EISSN

1755-3245

Publication Date

May 1, 2010

Volume

86

Issue

2

Start / End Page

274 / 282

Location

England

Related Subject Headings

  • Tunica Intima
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • Rats
  • RNA Interference
  • Proto-Oncogene Proteins c-akt
  • Protein Serine-Threonine Kinases
  • Phosphatidylinositol 3-Kinases
  • Phenotype
  • PTEN Phosphohydrolase