TNF induces phenotypic modulation in cerebral vascular smooth muscle cells: Implications for cerebral aneurysm pathology

Muhammad S. Ali, Robert M. Starke, Pascal M. Jabbour, Stavropoula I. Tjoumakaris, L. Fernando Gonzalez, Robert H. Rosenwasser, Gary K. Owens, Walter J. Koch, Nigel H. Greig, Aaron S. Dumont

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

Little is known about vascular smooth muscle cell (SMC) phenotypic modulation in the cerebral circulation or pathogenesis of intracranial aneurysms. Tumor necrosis factor-alpha (TNF) has been associated with aneurysms, but potential mechanisms are unclear. Cultured rat cerebral SMCs overexpressing myocardin induced expression of key SMC contractile genes (SM-actin, SM-22, smooth muscle myosin heavy chain), while dominant-negative cells suppressed expression. Tumor necrosis factor-alpha treatment inhibited this contractile phenotype and induced pro-inflammatory/matrix-remodeling genes (monocyte chemoattractant protein-1, matrix metalloproteinase-3, matrix metalloproteinase-9, vascular cell adhesion molecule-1, interleukin-1 beta). Tumor necrosis factor-alpha increased expression of KLF4, a known regulator of SMC differentiation. Kruppel-like transcription factor 4 (KLF4) small interfering RNA abrogated TNF- activation of inflammatory genes and suppression of contractile genes. These mechanisms were confirmed in vivo after exposure of rat carotid arteries to TNF- and early on in a model of cerebral aneurysm formation. Treatment with the synthesized TNF- inhibitor 3,6-dithiothalidomide reversed pathologic vessel wall alterations after induced hypertension and hemodynamic stress. Chromatin immunoprecipitation assays in vivo and in vitro demonstrated that TNF- promotes epigenetic changes through KLF4-dependent alterations in promoter regions of myocardin, SMCs, and inflammatory genes. In conclusion, TNF- induces phenotypic modulation of cerebral SMCs through myocardin and KLF4-regulated pathways. These results demonstrate a novel role for TNF- in promoting a pro-inflammatory/matrix-remodeling phenotype, which has important implications for the mechanisms behind intracranial aneurysm formation.

Original languageEnglish (US)
Pages (from-to)1564-1573
Number of pages10
JournalJournal of Cerebral Blood Flow and Metabolism
Volume33
Issue number10
DOIs
StatePublished - Oct 2013
Externally publishedYes

Keywords

  • Cerebral aneurysm
  • Cerebral vascular smooth muscle cells
  • Smooth muscle cell phenotypic modulation
  • TNF-alpha

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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