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