Patients with the connective tissue disorder Loeys-Dietz syndrome (LDS) are at high risk for aortic aneurysm. LDS results in the presence of missense mutations within either of the genes encoding receptors for TGF-β. LDS-associated mutations are predicted to reduce TGF-β signaling; however, aortic tissue samples from LDS patients indicate that TGF-β signaling may be enhanced.
In this issue of the Journal of Clinical Investigation , Harry Dietz and colleagues at Johns Hopkins School of Medicine developed a mouse model of LDS, in which transgenic animals expressing Tgfbr1 or Tgfbr2 with LDS-associated mutations recapitulated human phenotypes. Using this model, the authors determined that even though the mutated TGF-β receptors were functionally defective, there was evidence of increased TGF-β signaling as indicated by elevated Smad2 phosphorylation. Furthermore, development of aortic aneurysms in these mice was ameliorated by treatment with an Angiotensin II type 1 (AT1) receptor antagonist.
In a companion commentary, Alan Daughtery and colleagues at the University of Kentucky discuss the therapeutic implications of this study on the use of AT1 receptor agonists to treat LDS-associated aneurism.
TITLE: Angiotensin II–dependent TGF-β signaling contributes to Loeys-Dietz syndrome vascular pathogenesis
AUTHOR CONTACT: Elena Gallo MacFarlane
Johns Hopkins University School of Medicine, Baltimore, MD, USA
Phone: 4106148876; Fax: 4106142256; E-mail: galloem@gmail.com
View this article at http://www.jci.org/articles/view/69666?key=f036d148e02247c5f5d6
ACCOMPANYING COMMENTARY
TITLE: Aortic aneurysms in Loeys-Dietz syndrome — a tale of two pathways?
AUTHOR CONTACT: Alan Daugherty
University of Kentucky, Lexington, KY, USA
Phone: 8593233512; E-mail: alan.daugherty@uky.edu
View this article at: http://www.jci.org/articles/view/73906?key=fe840c2f4387dc7d0d58
Journal of Clinical Investigation