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 2

Tbr1MR/+ mice develop dilation of the aortic root in association with localized increase in TGF-β1 and TGF-β3 ligand expression.

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Tbr1MR/+ mice develop dilation of the aortic root in association with l...
(A) Immunoblot of lysates of the aortic root and ascending aorta of mice of the indicated genotypes at 24 weeks of age after probing with antibodies that recognize full-length latency-associated peptide (LAP)–TGF-β1, LAP–TGF-β2, LAP–TGF-β3; arrow identifies the band quantified for LAP–TGF-β3. Quantification after normalization to β-actin (same as that shown in in Figure 1F) is shown below (n = 3). P values refer to 1-way ANOVA followed by Holm-Sidak’s multiple comparisons test. (B) Representative RNA in situ hybridization of the aortic root of 24-week-old mice using RNAscope probes directed against the smooth muscle–specific transcript Myh11, and against Tgfb1 and Tgfb3; insets mark the area shown at higher magnification for each panel. Scale bars: 20 μm. Experiment was conducted at least 3 times. Image enhancement for visual display was applied uniformly to all panels. Numerical data are presented as scatter dot-plots with boxes, with the box denoting the mean; error bars identify the 95% confidence interval.