title: Aortopathy in a Mouse Model of Marfan Syndrome Is Not Mediated by Altered Transforming Growth Factor β Signaling.
abstract: Marfan syndrome (MFS) is caused by mutations in the gene encoding fibrillin-1 (FBN1); however, the mechanisms through which fibrillin-1 deficiency causes MFS-associated aortopathy are uncertain. Recently, attention was focused on the hypothesis that MFS-associated aortopathy is caused by increased transforming growth factor-β (TGF-β) signaling in aortic medial smooth muscle cells (SMC). However, there are many reasons to doubt that TGF-β signaling drives MFS-associated aortopathy. We used a mouse model to test whether SMC TGF-β signaling is perturbed by a fibrillin-1 variant that causes MFS and whether blockade of SMC TGF-β signaling prevents MFS-associated aortopathy.
  
  
  
  MFS mice (Fbn1C1039G/+genotype) were genetically modified to allow postnatal SMC-specific deletion of the type II TGF-β receptor (TBRII; essential for physiologic TGF-β signaling). In young MFS mice with and without superimposed deletion of SMC-TBRII, we measured aortic dimensions, histopathology, activation of aortic SMC TGF-β signaling pathways, and changes in aortic SMC gene expression. Young Fbn1C1039G/+mice had ascending aortic dilation and significant disruption of aortic medial architecture. Both aortic dilation and disrupted medial architecture were exacerbated by superimposed deletion of TBRII. TGF-β signaling was unaltered in aortic SMC of young MFS mice; however, SMC-specific deletion of TBRII in Fbn1C1039G/+mice significantly decreased activation of SMC TGF-β signaling pathways.
  
  
  
  In young Fbn1C1039G/+mice, aortopathy develops in the absence of detectable alterations in SMC TGF-β signaling. Loss of physiologic SMC TGF-β signaling exacerbates MFS-associated aortopathy. Our data support a protective role for SMC TGF-β signaling during early development of MFS-associated aortopathy.
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wei
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Jie Hong
authors.initials: JH
authors.lastname: Hu
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Stoyan N
authors.initials: SN
authors.lastname: Angelov
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Kate
authors.initials: K
authors.lastname: Fox
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.
authors.forename: James
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Enstrom
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Smith
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA ddichek@uw.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Dichek
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology*; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D000071838:Fibrillin-1 / Q000235:genetics*; D008382:Marfan Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C000605724:Fbn1 protein, mouse; D054392:Adipokines
keywords: Marfan syndrome; fibrillin‐1; gene expression; genetically altered mice; signaling pathways; transforming growth factor‐β pathway aneurysm