TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections
| Autor: | Dianna M. Milewicz, Andrea L. Lafont, Senthil Duraisamy, Xin-Hua Feng, Hazim J. Safi, Hariyadarshi Pannu, John E. Wiktorowicz, Anthony L. Estrera, Yao Yun Liang, John C. Carey, Callie S. Kwartler, Mark C. Hannibal, Filemon K. Tan, Sakiko Inamoto, Van Tran Fadulu, Marcia C. Willing |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Pathology
medicine.medical_specialty Physiology Smooth muscle cell differentiation Cellular differentiation Biology Protein Serine-Threonine Kinases medicine.disease_cause Transfection Muscle Smooth Vascular Cell Line Transforming Growth Factor beta1 Mice Physiology (medical) Calcium-binding protein medicine Animals Humans Genetic Predisposition to Disease Myofibroblasts Actin Cells Cultured Cell Proliferation Mutation Aortic Aneurysm Thoracic Calcium-Binding Proteins Microfilament Proteins Receptor Transforming Growth Factor-beta Type II Cell Differentiation Original Articles Calmodulin-binding proteins Actins Cell biology Aortic Dissection Phenotype Case-Control Studies cardiovascular system Calmodulin-Binding Proteins Signal transduction Cardiology and Cardiovascular Medicine Myofibroblast Receptors Transforming Growth Factor beta Signal Transduction |
| Popis: | Aims Transforming 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 results Using 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. Conclusions These 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. |
| Databáze: | OpenAIRE |
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