Angiotensin II-dependent TGF-? 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-? receptor gene (TGFBR1 or TGFBR2), which are predicted to result in diminished TGF-? signaling; however, aortic surgical samples from patients show evidence of paradoxically increased TGF-? 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-? in vitro, they maintained normal levels of Smad2 phosphorylation under steady-state culture conditions, suggesting a chronic compensation. Analysis of TGF-? signaling in the aortic wall in vivo revealed progressive upregulation of Smad2 phosphorylation and TGF-? target gene output, which paralleled worsening of aneurysm pathology and coincided with upregulation of TGF-?1 ligand expression. Importantly, suppression of Smad2 phosphorylation and TGF-?1 expression correlated with the therapeutic efficacy of the angiotensin II type 1 receptor antagonist losartan. Together, these data suggest that increased TGF-? signaling contributes to postnatal aneurysm progression in LDS.

SUBMITTER: Gallo EM 

PROVIDER: S-EPMC3871227 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature