Loeys-Dietz syndrome (LDS) is a connective tissue disorder that is characterized by a high risk for aneurysm and dissection throughout the arterial tree and phenotypically resembles Marfan syndrome. LDS is caused by heterozygous missense mutations in either TGF-β receptor gene (
Elena M. Gallo, David C. Loch, Jennifer P. Habashi, Juan F. Calderon, Yichun Chen, Djahida Bedja, Christel van Erp, Elizabeth E. Gerber, Sarah J. Parker, Kimberly Sauls, Daniel P. Judge, Sara K. Cooke, Mark E. Lindsay, Rosanne Rouf, Loretha Myers, Colette M. ap Rhys, Kathleen C. Kent, Russell A. Norris, David L. Huso, Harry C. Dietz
Submitter: Ziad Mallat | firstname.lastname@example.org
Authors: Alain Tedgui
University of Cambridge
Published January 6, 2014
Gallo et al. elegantly showed that mice harboring Loeys-Dietz syndrome (LDS) mutations in either Tgfbr1 or Tgfbr2, but not mice haplo-insufficient for Tgfbr alleles, recapitulated LDS phenotype, which was prevented by treatment with losartan. While the data are informative, we feel, the article is subject to interpretation bias regarding the role of TGF-β signaling in LDS pathogenesis.
Gallo et al. present evidence for a defective TGF-β receptor signaling in murine aortic LDS vascular smooth muscle cells (VSMCs) in vitro, which is recapitulated in VSMCs derived from LDS patients. Yet, they claim that chronic overcompensation occurs in vivo and drives the LDS phenotype. The authors have not definitively proven that the protective effect of losartan was mediated through suppression of TGF-β signaling. Indeed, there are 2 possible interpretations of their anti-TGF-β (1D11) treatment data (Supplementary Figures 10 and 11) that would indicate otherwise..
One explanation is that TGF-β blockade did not reduce p-Smad2 (compare p-Smad2 levels in 1D11-treated and placebo-treated Tgfbr2G357W/+ mice), meaning that the authors incorrectly attributed increased p-Smad2 to a paradoxical increase of TGF-β signaling. This is plausible because increased aortic p-Smad2 in aneurysm is not specific for Marfan or LDS but also occurs in aortic tissue of patients with non-syndromic aneurysms (1). Several previous studies indicate that the late increase of Smad2 (and p-Smad2) in syndromic and non-syndromic aneurysm is independent of TGF-β (2) and is driven by epigenetic regulation of the Smad2 promoter (3). Alternatively, the authors’ data suggest that 1D11 antibody blocked the increase of p-Smad2 in mutant mice compared to wild-type (WT) animals (compare the difference in p-Smad2 levels between WT and Tgfbr2G357W/+ mice treated with 1D11 or placebo in Supplementary Figure 10A), without significantly altering aortic growth, meaning that increased p-Smad2 in mutant mice does not contribute to LDS phenotype. Again, this is plausible because increased p-Smad2 occurs in settings unrelated to aortic aneurysm (e.g., Smad4 mutations of Myhre syndrome (4)). The authors’ data also suggest that chronic blockade of TGF-β can lead to paradoxical increase of p-Smad2 levels in WT mice (as high as p-Smad2 levels detected in untreated Tgfbr2G357W/+ mice, Supplementary Figure 10A) without inducing aortic pathology.
Thus, the authors' conclusion that “increased TGF-β signaling contributes to postnatal aneurysm progression in LDS” is not supported by the data. TGF-β might still promote aortic aneurysm in LDS; however, without direct evidence, this should be considered as one amongst other working hypotheses (5, 6).
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2. Gomez D, Coyet A, Ollivier V, Jeunemaitre X, Jondeau G, Michel JB, and Vranckx R. Epigenetic control of vascular smooth muscle cells in Marfan and non-Marfan thoracic aortic aneurysms. Cardiovasc Res. 2011;89(2):446-56.
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