Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome
Elena Gallo MacFarlane, … , Jennifer P. Habashi, Harry C. Dietz
Elena Gallo MacFarlane, … , Jennifer P. Habashi, Harry C. Dietz
Published February 5, 2019; First published January 7, 2019
Citation Information: J Clin Invest. 2019;129(2):659-675. https://doi.org/10.1172/JCI123547.
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Research Article Vascular biology

Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome

Abstract

The aortic root is the predominant site for development of aneurysm caused by heterozygous loss-of-function mutations in positive effectors of the transforming growth factor-β (TGF-β) pathway. Using a mouse model of Loeys-Dietz syndrome (LDS) that carries a heterozygous kinase-inactivating mutation in TGF-β receptor I, we found that the effects of this mutation depend on the lineage of origin of vascular smooth muscle cells (VSMCs). Secondary heart field–derived (SHF-derived), but not neighboring cardiac neural crest–derived (CNC-derived), VSMCs showed impaired Smad2/3 activation in response to TGF-β, increased expression of angiotensin II (AngII) type 1 receptor (Agtr1a), enhanced responsiveness to AngII, and higher expression of TGF-β ligands. The preserved TGF-β signaling potential in CNC-derived VSMCs associated, in vivo, with increased Smad2/3 phosphorylation. CNC-, but not SHF-specific, deletion of Smad2 preserved aortic wall architecture and reduced aortic dilation in this mouse model of LDS. Taken together, these data suggest that aortic root aneurysm predisposition in this LDS mouse model depends both on defective Smad signaling in SHF-derived VSMCs and excessive Smad signaling in CNC-derived VSMCs. This work highlights the importance of considering the regional microenvironment and specifically lineage-dependent variation in the vulnerability to mutations in the development and testing of pathogenic models for aortic aneurysm.

Authors

Elena Gallo MacFarlane, Sarah J. Parker, Joseph Y. Shin, Benjamin E. Kang, Shira G. Ziegler, Tyler J. Creamer, Rustam Bagirzadeh, Djahida Bedja, Yichun Chen, Juan F. Calderon, Katherine Weissler, Pamela A. Frischmeyer-Guerrerio, Mark E. Lindsay, Jennifer P. Habashi, Harry C. Dietz

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Figure 9

CNC-specific Smad2 deletion associates with decreased Smad2/3 phosphorylation in the aortic root of Tbr1MR/+ mice.

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CNC-specific Smad2 deletion associates with decreased Smad2/3 phosphoryl...
(A) Representative immunofluorescence (IF) images of the aortic root of 20-week-old control mice (Tbr1+/+; Sm2Ctrl), mutant mice in which Smad2 is not deleted (Tbr1MR/+; Sm2Ctrl), and mutant mice in which Smad2 is deleted in SHF-derived cells (Tbr1MR/+; Sm2SHF) stained with an antibody that recognizes p-Smad2 or p-Smad2/3. Dotted lines mark the outer boundary of the vessel wall. Experiment was conducted at least 3 times. Image enhancement for visual display was applied uniformly to all panels. (B) Representative IF images of the aortic root of 20-week-old control mice (Tbr1+/+; Sm2Ctrl), mutant mice (Tbr1MR/+; Sm2Ctrl), and mutant mice in which Smad2 is deleted in CNC-derived cells (Tbr1MR/+; Sm2CNC) stained with an antibody that recognizes p-Smad2 or p-Smad2/3. Scale bars: 50 μm. Experiment was conducted at least 3 times. Image enhancement for visual display was applied uniformly to all panels.