TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections

Sakiko Inamoto, Callie S. Kwartler, Andrea L. Lafont, Yao Yun Liang, Van Tran Fadulu, Senthil Duraisamy, Marcia Willing, Anthony Estrera, Hazim Safi, Mark C. Hannibal, John Carey, John Wiktorowicz, Filemon K. Tan, Xin Hua Feng, Hariyadarshi Pannu, Dianna M. Milewicz

    Research output: Contribution to journalArticle

    77 Scopus citations

    Abstract

    AimsTransforming growth factor-β (TGF-β) signaling is critical for the differentiation of smooth muscle cells (SMCs) into quiescent cells expressing a full repertoire of contractile proteins. Heterozygous mutations in TGF-β receptor type II (TGFBR2) disrupt TGF-β signaling and lead to genetic conditions that predispose to thoracic aortic aneurysms and dissections (TAADs). The aim of this study is to determine the molecular mechanism by which TGFBR2 mutations cause TAADs.Methods and resultsUsing aortic SMCs explanted from patients with TGFBR2 mutations, we show decreased expression of SMC contractile proteins compared with controls. Exposure to TGF-β1 fails to increase expression of contractile genes in mutant SMCs, whereas control cells further increase expression of these genes. Analysis of fixed and frozen aortas from patients with TGFBR2 mutations confirms decreased in vivo expression of contractile proteins relative to unaffected aortas. Fibroblasts explanted from patients with TGFBR2 mutations fail to transform into mature myofibroblasts with TGF-β1 stimulation as assessed by expression of contractile proteins.ConclusionsThese data support the conclusion that heterozygous TGFBR2 mutations lead to decreased expression of SMC contractile protein in both SMCs and myofibroblasts. The failure of TGFBR2-mutant SMCs to fully express SMC contractile proteins predicts defective contractile function in these cells and aligns with a hypothesis that defective SMC contractile function contributes to the pathogenesis of TAAD.

    Original languageEnglish (US)
    Pages (from-to)520-529
    Number of pages10
    JournalCardiovascular research
    Volume88
    Issue number3
    DOIs
    StatePublished - Dec 1 2010

    Keywords

    • Myofibroblast
    • Smooth muscle cell differentiation
    • TGF-β
    • TGFBR2 mutations
    • Thoracic aortic aneurysms and dissections

    ASJC Scopus subject areas

    • Physiology
    • Cardiology and Cardiovascular Medicine
    • Physiology (medical)

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  • Cite this

    Inamoto, S., Kwartler, C. S., Lafont, A. L., Liang, Y. Y., Fadulu, V. T., Duraisamy, S., Willing, M., Estrera, A., Safi, H., Hannibal, M. C., Carey, J., Wiktorowicz, J., Tan, F. K., Feng, X. H., Pannu, H., & Milewicz, D. M. (2010). TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections. Cardiovascular research, 88(3), 520-529. https://doi.org/10.1093/cvr/cvq230