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Background  Marfan syndrome ( MFS ) is caused by mutations in the gene encoding fibrillin‐1 (  FBN 1 ); 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.    Methods and Results   MFS  mice ( Fbn1  C1039G/+  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  Fbn1  C1039G/+  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  Fbn1  C1039G/+  mice significantly decreased activation of  SMC TGF ‐β signaling pathways.    Conclusions  In young  Fbn1  C1039G/+  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.

Aortopathy in a Mouse Model of Marfan Syndrome Is Not Mediated by Altered Transforming Growth Factor β Signaling