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 encodingfibrillin-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-beta (TGF-beta) signaling in aortic medial smooth muscle cells (SMC). However, there are many reasons to doubt that TGF-beta signaling drives MFS-associated aortopathy. We used a mouse model to test whether SMC TGF-beta signaling is perturbed by a fibrillin-1 variant that causes MFS and whether blockade of SMC TGF-beta signaling prevents MFS-associated aortopathy. Methods and Results-MFS mice (Fbn1(C) (1039G/+) genotype) were genetically modified to allow postnatal SMC-specific deletion of the type II TGF-beta receptor (TBRII; essential for physiologic TGF-beta signaling). In young MFS mice with and without superimposed deletion of SMC-TBRII, we measured aortic dimensions, histopathology, activation of aortic SMC TGF-beta 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- b 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-beta signaling pathways. Conclusions-In young Fbn1(C1039G/+) mice, aortopathy develops in the absence of detectable alterations in SMC TGF-beta signaling. Loss of physiologic SMC TGF-beta signaling exacerbates MFS-associated aortopathy. Our data support a protective role for SMC TGF-beta signaling during early development of MFS- associated aortopathy.