TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections
Open Access
- 13 July 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Cardiovascular Research
- Vol. 88 (3), 520-529
- https://doi.org/10.1093/cvr/cvq230
Abstract
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. 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. 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.Keywords
This publication has 33 references indexed in Scilit:
- Transforming Growth Factor-β-activated Kinase 1 Is an Essential Regulator of Myogenic DifferentiationPublished by Elsevier BV ,2010
- Fibulin-4 Deficiency Results in Ascending Aortic AneurysmsCirculation Research, 2010
- Noncanonical TGF-β pathways, mTORC1 and Abl, in renal interstitial fibrogenesisAmerican Journal of Physiology-Renal Physiology, 2010
- Non-Smad pathways in TGF-β signalingCell Research, 2008
- Intimal Smooth Muscle Cells of Porcine and Human Coronary Artery Express S100A4, a Marker of the Rhomboid Phenotype In VitroCirculation Research, 2007
- MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin IIHuman Molecular Genetics, 2007
- Aneurysm Syndromes Caused by Mutations in the TGF-β ReceptorNew England Journal of Medicine, 2006
- Characterization of the inflammatory and apoptotic cells in the aortas of patients with ascending thoracic aortic aneurysms and dissectionsThe Journal of Thoracic and Cardiovascular Surgery, 2006
- Cardiovascular malformations with normal smooth muscle differentiation in neural crest-specific type II TGFβ receptor (Tgfbr2) mutant miceDevelopmental Biology, 2006
- Transforming Growth Factor-β-Induced Differentiation of Smooth Muscle From a Neural Crest Stem Cell LineCirculation Research, 2004