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

Abstract

BackgroundMarfan 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 (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.ConclusionsIn 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.

NEDD9 targets COL3A1 to promote endothelial fibrosis and pulmonary arterial hypertension

“…However, perturbations to TGF-β biofunctionality are associated with collagen deposition patterns that vary across cell types (2), and within patients who share circumspect clinical phenotypes (3). This heterogeneity suggests that the TGF-β ‘master switch’ theory may be an insufficient construct by which to understand fibrosis globally.…”

TGF-β (Transforming Growth Factor-β) Signaling Protects the Thoracic and Abdominal Aorta From Angiotensin II-Induced Pathology by Distinct Mechanisms

“…The 42% reduction in western blot signal for TBRII differs from the near-complete ablation of the receptor that we documented (in 2 independent studies) by western blotting of aortic media of the same line of tamoxifen-treated bi-transgenic mice. 13, 47 In one of these studies we also documented that aortic SMC of these mice have impaired canonical and non-canonical TGF-β signaling. 47 The apparently lower degree of receptor loss in the present study is likely due to adventitial cell contamination of the aortic medial peels (a technical issue).…”

“…13, 47 In one of these studies we also documented that aortic SMC of these mice have impaired canonical and non-canonical TGF-β signaling. 47 The apparently lower degree of receptor loss in the present study is likely due to adventitial cell contamination of the aortic medial peels (a technical issue). This explanation is supported by measurements of mRNA in medial peels from mice from the blood-pressure cohort of the present study: mice with SMC-specific Tgfbr2 deletion had significantly higher levels of Myh11 , Tagln , and LoxL1 mRNA than control mice (data not shown).…”

Further Evidence Supporting a Protective Role of Transforming Growth Factor-β (TGFβ) in Aortic Aneurysm and Dissection

“…Initial studies in AngII-infused or Fbn1 C1041G/+ mice demonstrated that inhibition of TGFβ signaling by neutralizing antibodies or pharmacological agents modestly inhibited thoracic aortic aneurysm formation [5–7]. However, several subsequent studies have shown that TGFβ neutralization markedly increased aortic aneurysm size and rupture in AngII-infused or Fbn1 mgR/mgR mice [8–10] and that conditional deletion of Tgfbr2 in smooth muscle cells greatly induced spontaneous aortic aneurysm and dissection and aggravated the aortopathy of Fbn1 C1041G/+ mice [11–13]. Thus, there is conflicting evidence for pathogenic versus protective roles for TGFβ in aortic disease.…”

“…The findings of this new study by the Dichek group compared to previous studies are summarized in Table 1. Although it has previously been shown that TGFβ protects the abdominal aorta from AngII-mediated disease through effects on cell types other than SMCs [8] and that TGFβ signaling in SMCs protects the thoracic aorta from spontaneous or mutant Fbn1 -mediated disease [11–13], the advance of this new study is that the effects of systemic and conditional inhibition of TGFβ signaling in both the thoracic and abdominal aorta are compared in the same murine model of AngII-mediated aortic disease. However, key differences with previous studies are highlighted by the authors in which they consider technical factors as explanations.…”