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

• Published in: Journal of cardiovascular development and disease 2024-11, Vol.11 (11), p.349
• Main Authors: Lin, Chien-Jung, Keating, Campbell, Roth, Robyn, Caliskan, Yasar, Nazzal, Mustafa, Exil, Vernat, DiPaolo, Richard, Verma, Divya Ratan, Harjai, Kishore, Zayed, Mohamed, Lin, Chieh-Yu, Mecham, Robert P, Jain, Ajay K
• Format: Article
• Language: English
• Subjects: Abdomen; Aneurysms; aortic aneurysm; Aortic aneurysms; Atherosclerosis; B cells; Cells; Coronary vessels; Datasets; DNA binding proteins; Ethylenediaminetetraacetic acid; Extracellular matrix; Gene expression; Genes; Genetic engineering; Protein binding; Quality control; RNA; RNA sequencing; single-cell RNA sequencing; Smooth muscle; smooth muscle cell; Transcription factors
• ISSN: 2308-3425; 2308-3425
• DOI: 10.3390/jcdd11110349

Thoracic and abdominal aortic aneurysms (TAAs and AAAs, respectively) share morphological features but have distinct clinical and hereditary characteristics. Studies using bulk RNA comparisons revealed distinct patterns of gene expression in human TAA and AAA tissues. However, given the summative nature of bulk RNA studies, these findings represent the totality of gene expression without regards to the differences in cellular composition. Single-cell RNA sequencing provides an opportunity to interrogate cell-type-specific transcriptomes. Single cell RNA sequencing datasets from mouse TAA (GSE153534) and AAA (GSE164678 and GSE152583) with respective controls were obtained from the Gene Expression Omnibus. Bioinformatic analysis was performed with the Seurat 4, clusterProfiler, and Connectome software packages (V1.0.1). Immunostaining was performed with standard protocols. Within normal and aneurysmal aortae, three unique populations of cells that express smooth muscle cell (SMC) markers were identified (SMC1, SMC2, and SMCmod). A greater proportion of TAA SMCs clustered as a unique population, SMCmod, relative to the AAA SMCs (38% vs. 10-12%). These cells exhibited transcriptional features distinct from other SMCs, which were characterized by and expression. Genes upregulated in TAA SMCs were enriched for the Reactome terms "extracellular matrix organization" and "insulin-like growth factor (IGF) transport and uptake by IGF binding proteins (IGFBPs)", indicating a role for in TAA pathogenesis. Regulon analysis revealed transcription factors enriched in TAAs and AAAs. Validating these mouse bioinformatic findings, immunostaining demonstrated that both IGFBP2 and TNFRSF11B proteins increased in human TAAs compared to AAAs. These results highlight the unique cellular composition and transcriptional signature of SMCs in TAAs and AAAs. Future studies are needed to reveal the pathogenetic pathways of and .