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 (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.


METHODS AND RESULTS
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.


CONCLUSIONS
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.
['Wei|Hao|H|', 'Hu|Jie Hong|JH|', 'Angelov|Stoyan N|SN|', 'Fox|Kate|K|', 'Yan|James|J|', 'Enstrom|Rachel|R|', 'Smith|Alexandra|A|', 'Dichek|David A|DA|']
D000818:Animals D001011:Aorta D017545:Aortic Aneurysm, Thoracic D001018:Aortic Diseases D004195:Disease Models, Animal D000071838:Fibrillin-1 D008382:Marfan Syndrome D051379:Mice D009131:Muscle, Smooth, Vascular D032389:Myocytes, Smooth Muscle D017346:Protein Serine-Threonine Kinases D000077294:Receptor, Transforming Growth Factor-beta Type II D018125:Receptors, Transforming Growth Factor beta D015398:Signal Transduction D016212:Transforming Growth Factor beta
Marfan syndrome signaling pathways gene expression fibrillin‐1 genetically altered mice transforming growth factor‐β pathway aneurysm