Angiotensin II–dependent TGF-β signaling contributes to Loeys-Dietz syndrome vascular pathogenesis
Elena M. Gallo, … , David L. Huso, Harry C. Dietz
Elena M. Gallo, … , David L. Huso, Harry C. Dietz
Published December 20, 2013
Citation Information: J Clin Invest. 2014;124(1):448-460. https://doi.org/10.1172/JCI69666.
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Angiotensin II–dependent TGF-β signaling contributes to Loeys-Dietz syndrome vascular pathogenesis

Abstract

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 (TGFBR1 or TGFBR2), which are predicted to result in diminished TGF-β signaling; however, aortic surgical samples from patients show evidence of paradoxically increased TGF-β signaling. We generated 2 knockin mouse strains with LDS mutations in either Tgfbr1 or Tgfbr2 and a transgenic mouse overexpressing mutant Tgfbr2. Knockin and transgenic mice, but not haploinsufficient animals, recapitulated the LDS phenotype. While heterozygous mutant cells had diminished signaling in response to exogenous TGF-β in vitro, they maintained normal levels of Smad2 phosphorylation under steady-state culture conditions, suggesting a chronic compensation. Analysis of TGF-β signaling in the aortic wall in vivo revealed progressive upregulation of Smad2 phosphorylation and TGF-β target gene output, which paralleled worsening of aneurysm pathology and coincided with upregulation of TGF-β1 ligand expression. Importantly, suppression of Smad2 phosphorylation and TGF-β1 expression correlated with the therapeutic efficacy of the angiotensin II type 1 receptor antagonist losartan. Together, these data suggest that increased TGF-β signaling contributes to postnatal aneurysm progression in LDS.

Authors

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

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Figure 1

Mouse models of TGF-β receptor haploinsufficiency and LDS.

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Mouse models of TGF-β receptor haploinsufficiency and LDS. (A) Structure...
(A) Structure of Tgfbr1 and Tgfbr2 mutant alleles in haploinsufficient mouse models. A stop mutation is present in exon 7 of the Tgfbr1 mutant allele; a NeoR replaces part of exon 4 in the Tgfbr2 mutant allele, creating a frameshift. These alterations result in an approximately 50% reduction in expression of the corresponding cDNA in aortic tissue derived from Tgfbr1+/– and Tgfbr2+/– haploinsufficient mice, as assessed by RT-PCR and indicated underneath the blots. (B) Structure of the Tgfbr1M318R mutant allele. ES cell targeting was verified by Southern blot. Expression of the mutant cDNA in aortic tissue derived from Tgfbr1M318R/+ mice was verified by RT-PCR. NciI restriction digest allows for discrimination of wild-type and mutant cDNA (the black line indicates lanes that were run on the same gel but were noncontiguous). (C) Schematic illustrating the genomic structure of the Tgfbr2G357W mutant allele. ES cell targeting was verified by Southern blot. Expression of the mutant cDNA in aortic tissue derived from Tgfbr2G357W/+ mice was evaluated by RT-PCR. AlwI restriction digest allows for discrimination of wild-type and mutant cDNA.