Aortic aneurysms in Loeys-Dietz syndrome — a tale of two pathways?
Frank Davis, … , Debra L. Rateri, Alan Daugherty
Frank Davis, … , Debra L. Rateri, Alan Daugherty
Published December 20, 2013
Citation Information: J Clin Invest. 2014;124(1):79-81. https://doi.org/10.1172/JCI73906.
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Commentary

Aortic aneurysms in Loeys-Dietz syndrome — a tale of two pathways?

Abstract

Loeys-Dietz syndrome (LDS) is a connective tissue disorder that is characterized by skeletal abnormalities, craniofacial malformations, and a high predisposition for aortic aneurysm. In this issue of the JCI, Gallo et al. developed transgenic mouse strains harboring missense mutations in the genes encoding type I or II TGF-β receptors. These mice exhibited several LDS-associated phenotypes. Despite being functionally defective, the mutated receptors enhanced TGF-β signaling in vivo, inferred by detection of increased levels of phosphorylated Smad2. Aortic aneurysms in these LDS mice were ablated by treatment with the Ang II type 1 (AT1) receptor antagonist losartan. The results from this study will foster further interest into the potential therapeutic implications of AT1 receptor antagonists.

Authors

Frank Davis, Debra L. Rateri, Alan Daugherty

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Figure 1

Convergence of the TGF-β and Ang II signaling pathways is implicated in TAA.

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Convergence of the TGF-β and Ang II signaling pathways is implicated in ...
Missense mutations in either the TGF-β receptor (TGFR) type 1 or 2 subtypes, specifically Tgfbr2G357W and Tgfbr1M318R, lead to increased abundance of pSmad2 and pERK in mouse models of LDS. The increase in these activated proteins correlates with increased elastin fragmentation and aortic root dilation. Administration of losartan, an ARB, suppressed Smad2 and ERK phosphorylation and prevented aortic dilation. However, important mechanistic questions remain. (i) Why does administration of a TGF-β–neutralizing antibody (1D11 Nab) fail to reduce aortic root dilation? (ii) How does defective TGF-β signaling augment AT1R stimulation? (iii) How do functionally defective TGF-β receptors promote increased phosphorylation of Smad2 and ERK? (iv) What are the downstream targets of pSmad2 and pERK that cause elastin fragmentation and subsequent aortic aneurysm?