Journal Article

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

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

2019

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Aneurysm / Aneurysms / Angiotensin / Angiotensin II / Angiotensins / Animal models / Animals / Aortic aneurysm / Aortic aneurysms / Bioavailability / Biomedical research / Bone morphogenetic proteins / Cellular signal transduction / Clonal deletion / Coronary vessels / Development and progression / Disease Models, Animal / Gene mutation / Genetic aspects / Genetic disorders / Growth factors / Humans / Kinases / Ligands / Loeys-Dietz Syndrome - embryology / Loeys-Dietz Syndrome - genetics / Loeys-Dietz Syndrome - pathology / Marfan syndrome / Mice / Mice, Mutant Strains / Muscle, Smooth, Vascular - metabolism / Muscle, Smooth, Vascular - pathology / Mutation / Myocytes, Smooth Muscle - metabolism / Myocytes, Smooth Muscle - pathology / Neural crest / Pathogenesis / Phosphorylation / Receptor, Angiotensin, Type 1 - genetics / Receptor, Angiotensin, Type 1 - metabolism / Signal Transduction / Smad protein / Smad2 protein / Smad2 Protein - genetics / Smad2 Protein - metabolism / Smad3 Protein - genetics / Smooth muscle / Transforming growth factor / Transforming growth factor-b / Transforming growth factors