Back to Search
Start Over
Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2019 Feb 01; Vol. 129 (2), pp. 659-675. Date of Electronic Publication: 2019 Jan 07. - Publication Year :
- 2019
-
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.
- Subjects :
- Animals
Disease Models, Animal
Humans
Loeys-Dietz Syndrome genetics
Loeys-Dietz Syndrome pathology
Mice
Mice, Mutant Strains
Muscle, Smooth, Vascular pathology
Myocytes, Smooth Muscle pathology
Receptor, Angiotensin, Type 1 genetics
Smad2 Protein genetics
Smad3 Protein genetics
Loeys-Dietz Syndrome embryology
Muscle, Smooth, Vascular metabolism
Myocytes, Smooth Muscle metabolism
Receptor, Angiotensin, Type 1 metabolism
Signal Transduction
Smad2 Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 129
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 30614814
- Full Text :
- https://doi.org/10.1172/JCI123547