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

Elena Gallo MacFarlane1,2, Sarah J Parker1,3, Joseph Y Shin4

  • 1McKusick-Nathans Institute of Genetic Medicine.

The Journal of Clinical Investigation
|January 8, 2019
PubMed

Insights

Aortic root aneurysms in Loeys-Dietz syndrome depend on vascular smooth muscle cell origin. Defective TGF-β signaling in some cells and excessive signaling in others contribute to aneurysm development.

Area of Science:

  • Cardiovascular Biology
  • Developmental Biology
  • Genetics

Background:

  • Aortic root aneurysms are linked to mutations in the transforming growth factor-β (TGF-β) pathway.
  • Loeys-Dietz syndrome (LDS) involves heterozygous loss-of-function mutations affecting TGF-β signaling.

Purpose of the Study:

  • To investigate the role of vascular smooth muscle cell (VSMC) lineage in aortic aneurysm development in a mouse model of LDS.
  • To understand how TGF-β receptor I mutations impact VSMCs from different developmental origins.

Main Methods:

  • Utilized a mouse model with a kinase-inactivating mutation in TGF-β receptor I.
  • Analyzed Smad2/3 activation, angiotensin II receptor expression, and TGF-β ligand levels in different VSMC lineages.
  • Performed lineage-specific gene deletion (Smad2) to assess functional impact.

Main Results:

  • SHF-derived VSMCs showed impaired TGF-β/Smad2/3 signaling, increased AngII receptor expression, and higher TGF-β ligand levels.
  • CNC-derived VSMCs exhibited preserved TGF-β signaling and increased Smad2/3 phosphorylation in vivo.
  • Smad2 deletion specifically in CNC-derived VSMCs preserved aortic architecture and reduced dilation.

Conclusions:

  • Aortic root aneurysm predisposition in this LDS model is influenced by both defective TGF-β signaling in SHF-derived VSMCs and excessive signaling in CNC-derived VSMCs.
  • Lineage-dependent variations in VSMC response to TGF-β are critical in aortic aneurysm pathogenesis.
  • This highlights the importance of regional microenvironment and cell-type specificity in studying aneurysm development.
Keywords:
Monogenic diseasesMouse modelsSignal transductionVascular Biology

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