| First Author | Gallo EM | Year | 2014 |
| Journal | J Clin Invest | Volume | 124 |
| Issue | 1 | Pages | 448-60 |
| PubMed ID | 24355923 | Mgi Jnum | J:204960 |
| Mgi Id | MGI:5543792 | Doi | 10.1172/JCI69666 |
| Citation | Gallo EM, et al. (2014) Angiotensin II-dependent TGF-beta signaling contributes to Loeys-Dietz syndrome vascular pathogenesis. J Clin Invest 124(1):448-60 |
| abstractText | 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-beta1 ligand expression. Importantly, suppression of Smad2 phosphorylation and TGF-beta1 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. |
