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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Categories: 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 3

SHF- and CNC-derived VSMCs intermingle in the aortic root of Tbr1MR/+ mice.

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SHF- and CNC-derived VSMCs intermingle in the aortic root of Tbr1MR/+ mi...
(A) Schematic representation of the aortic root and arch highlighting the embryonic origin of VSMCs that populate the medial layer in these regions. (B) Schematic representation of mouse transgenic lines used for tracing of SHF- and CNC-derived VSMCs. Mice carrying a conditional STOP cassette controlling expression of a fluorescent reporter were crossed to mice that express the Cre recombinase under the control of the SHF-specific promoter Mef2cSHF or CNC-specific promoter Wnt1. Removal of the STOP cassette induces expression of the fluorescent reporter and allows identification of VSMCs derived from the lineage of interest even after these promoters are silenced postnatally. (C) Representative fluorescence images of the aorta of control (Tbr1+/+) and mutant (Tbr1MR/+) mice in which SHF- and CNC-derived cells are lineage-traced based on TdTomato fluorescence; insets mark the areas in the ascending aorta and aortic root shown at higher magnification to the right of each panel. SHF- and CNC-derived VSMCs intermingle in the aortic root, with relative polarization towards the adventitial and luminal margins of the media, respectively. Scale bars: 200 μm. Image enhancement for visual display was applied uniformly to all panels. Experiment was conducted at least 3 times.