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

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.