Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 33, Issue 10, Pages 1564-1573Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/jcbfm.2013.109
Keywords
Cerebral aneurysm; Cerebral vascular smooth muscle cells; Smooth muscle cell phenotypic modulation; TNF-alpha
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Funding
- NIH [K08NS067072, R01 HL57353, R01 HL098538, R01 HL087867, P01 HL091799, P01 HL07544]
- Intramural Research Program of NIH
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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-alpha) has been associated with aneurysms, but potential mechanisms are unclear. Cultured rat cerebral SMCs overexpressing myocardin induced expression of key SMC contractile genes (SM-alpha-actin, SM-22 alpha, 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-alpha activation of inflammatory genes and suppression of contractile genes. These mechanisms were confirmed in vivo after exposure of rat carotid arteries to TNF-alpha and early on in a model of cerebral aneurysm formation. Treatment with the synthesized TNF-alpha 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-alpha promotes epigenetic changes through KLF4-dependent alterations in promoter regions of myocardin, SMCs, and inflammatory genes. In conclusion, TNF-alpha induces phenotypic modulation of cerebral SMCs through myocardin and KLF4-regulated pathways. These results demonstrate a novel role for TNF-alpha in promoting a pro-inflammatory/matrix-remodeling phenotype, which has important implications for the mechanisms behind intracranial aneurysm formation.
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