Distinct Patterns of Smooth Muscle Phenotypic Modulation in Thoracic and Abdominal Aortic Aneurysms

Area of Science:

• Vascular Biology
• Genomics
• Proteomics

Background:

• Thoracic aortic aneurysms (TAAs) and abdominal aortic aneurysms (AAAs) share morphological similarities but differ in clinical and hereditary aspects.
• Bulk RNA sequencing studies show distinct gene expression patterns in TAA and AAA tissues, but lack cellular resolution.
• Single-cell RNA sequencing (scRNA-seq) enables interrogation of cell-type-specific transcriptomes, crucial for understanding complex diseases like aortic aneurysms.

Purpose of the Study:

• To investigate the cell-type-specific transcriptomic differences between thoracic and abdominal aortic aneurysms using scRNA-seq.
• To identify unique cell populations and molecular signatures associated with TAA and AAA pathogenesis.
• To validate key findings in human aortic tissues.

Main Methods:

• Acquisition and analysis of scRNA-seq datasets from mouse TAA and AAA models, along with controls, from the Gene Expression Omnibus.
• Bioinformatic analysis using Seurat 4, clusterProfiler, and Connectome software.
• Immunostaining of human aortic tissues to validate protein expression levels of key identified markers.

Main Results:

• Identification of three distinct smooth muscle cell (SMC) populations (SMC1, SMC2, SMCmod) in normal and aneurysmal aortae.
• A significantly higher proportion of SMCmod cells (38%) was observed in TAAs compared to AAAs (10-12%).
• SMCmod cells exhibited distinct transcriptional features, including upregulated expression of *Igfbp2* and *Tnfrsf11b*, and enrichment for pathways related to extracellular matrix organization and IGF transport.

Conclusions:

• TAAs and AAAs possess unique cellular compositions and transcriptomic signatures within their SMC populations.
• The *Igfbp2* and *Tnfrsf11b* genes are significantly associated with TAA SMCs and may play a role in TAA pathogenesis.
• Further research is warranted to elucidate the specific pathogenetic roles of *IGFBP2* and *TNFRSF11B* in aortic aneurysm development.