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

Cardiovascular Research
Sakiko InamotoD M Milewicz

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 SM...Continue Reading

References

Apr 30, 1996·Proceedings of the National Academy of Sciences of the United States of America·S K MasurS Petridou
Jan 15, 1999·Acta Physiologica Scandinavica·J V Small, M Gimona
Jul 6, 2004·Nature Genetics·Takeshi MizuguchiNaomichi Matsumoto
Jul 23, 2004·Physiological Reviews·Gary K OwensBrian R Wamhoff
Aug 13, 2004·American Journal of Physiology. Cell Physiology·Sanjay SinhaGary K Owens
Jun 28, 2005·The Journal of Biological Chemistry·Rebecca A DeatonStephen R Grant
Aug 2, 2005·Seminars in Cell & Developmental Biology·Jason Z Stoller, Jonathan A Epstein
Dec 1, 2005·The Journal of Biological Chemistry·Shiyou ChenRobert J Lechleider
Mar 25, 2006·Development·Joy L JadrichElectra Coucouvanis
Aug 25, 2006·The New England Journal of Medicine·Bart L LoeysHarry C Dietz
Mar 24, 2007·Arteriosclerosis, Thrombosis, and Vascular Biology·Mark W Majesky
Jun 12, 2008·Annual Review of Genomics and Human Genetics·Dianna M MilewiczHariyadarshi Pannu
Dec 31, 2008·Cell Research·Ying E Zhang
Oct 23, 2009·American Journal of Physiology. Renal Physiology·Shinong WangRaimund Hirschberg
Dec 29, 2009·The Journal of Biological Chemistry·Shephali BhatnagarAshok Kumar

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Citations

Nov 7, 2013·European Journal of Human Genetics : EJHG·Ruth LeutermannGeorg Rosenberger
Aug 30, 2013·Cardiovascular Research·Emanuela BranchettiGiovanni Ferrari
Jan 25, 2012·The Journal of Clinical Investigation·Dianna M Milewicz
Jan 10, 2014·The Journal of Clinical Investigation·Wei LiGeorge Tellides
Mar 16, 2013·Biomechanics and Modeling in Mechanobiology·Sara RoccabiancaJay D Humphrey
Mar 9, 2012·Cardiology Research and Practice·Seamus C HarrisonSteve E Humphries
Mar 8, 2013·Cardiovascular Pathology : the Official Journal of the Society for Cardiovascular Pathology·Matteo CoenMarie-Luce Bochaton-Piallat
May 4, 2011·Birth Defects Research. Part A, Clinical and Molecular Teratology·Helen M Arthur, Simon D Bamforth
Aug 8, 2015·Human Mutation·Dimitra MichaFleur S van Dijk
Aug 6, 2013·American Journal of Human Genetics·Dong-chuan GuoDianna M Milewicz
Nov 8, 2011·American Journal of Human Genetics·Matthew J BownNilesh J Samani
Jun 13, 2013·Clinical Biochemistry·Lee StonerJames Faulkner
Oct 12, 2014·BMC Cardiovascular Disorders·Yang YuanShengdong Huang
Sep 29, 2017·Physiological Reviews·Patrick LacolleyStéphane Laurent
Nov 24, 2016·Arteriosclerosis, Thrombosis, and Vascular Biology·Dianna M MilewiczJames T Stull
Jun 15, 2016·Circulation·Eric M IsselbacherMark E Lindsay
Apr 11, 2015·Circulation Research·Jay D HumphreyDianna M Milewicz
May 13, 2015·Circulation Research·Mara Martín-AlonsoAlicia G Arroyo
Jan 27, 2017·Arteriosclerosis, Thrombosis, and Vascular Biology·Alicia N Lyle, Uwe Raaz
Jan 17, 2015·Arteriosclerosis, Thrombosis, and Vascular Biology·Eva Crosas-MolistGustavo Egea
Jan 18, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Dianna M Milewicz, Francesco Ramirez
Feb 15, 2019·Circulation Research·Amélie PinardDianna M Milewicz
Mar 10, 2018·Nature Communications·Christian L Lino CardenasMark E Lindsay
Sep 3, 2019·Molecular Genetics & Genomic Medicine·Luc CozijnsenDimitra Micha

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