Journal Article

Angiotensin II-dependent TGF-Beta signaling contributes to Loeys-Dietz syndrome vascular pathogenesis

Parker, Sarah J, Dietz, Harry C, Loch, David C, Gerber, Elizabeth E, Rouf, Rosanne, Norris, Russell A, Huso, David L, Gallo, Elena M, Kent, Kathleen C, Chen, Yichun, Judge, Daniel P, Calderon, Juan F, van Erp, Christel, Sauls, Kimberly, Habashi, Jennifer P, Bedja, Djahida, Cooke, Sara K, Myers, Loretha, Rhys, Colette M Ap, Lindsay, Mark E

2014

Overview

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-bgr; signaling. In this paper, the authors 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. The 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, the suppression of Smad2 phosphorylation and TGF-β1 expression correlated with the therapeutic efficacy of the angiotensin II type 1 receptor antagonist losartan.

• Publisher: American Society for Clinical Investigation
• Subject: Age / Biomedical research / Cloning / Dissection / Genes / Kinases / Mutation / Rodents / Studies / Substance abuse treatment