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Smooth muscle cells in atherosclerosis-prone and resistant regions of the aorta of C57Bl/6 mice at age of 4 months

ABSTRACT: This study compared gene expression in smooth muscle cells (SMCs) in atherosclerosis-prone and atherosclerosis-resistant regions of the aorta of C57Bl/6 mice. In a parallel experiment, both regions were compared in young, plaque-free apolipoprotein E-deficient (apoE-/-) mice. Aortas of 3 male and 3 female C57Bl6 mice were isolated, perfused with triton X-100 to remove endothelial cells and divided in an atherosclerosis-prone region (AA: ascending aorta, aortic arch and proximal 2 mm of thoracic aorta) and an atherosclerosis-resistant region (TA: central thoracic aorta,i.e. 6 mm distal from the proximal 2mm of the thoracic aorta). Microarray analysis (VIB-MAF) of pooled total RNA showed differential expression (>2-fold difference) for 70 genes. Up- or downregulation in the AA was observed for 33 and 37 genes respectively. Differential expression of 3 genes (ATPase, Na+/K+ transporting, beta 1 polypeptide, sarcolipin and homeo box B7) was confirmed using real-time PCR. Twenty five genes showed exclusively differential expression in C57BL6 mice. Only 7 could be linked to specific processes: development (4) and cell growth (3). The other 18 genes were all involved in different processes. Among the 45 genes showing differential expression in C57Bl/6 as well as apoE-/- mice, most were related to development (13), cell growth (8) and transcription (10). These results point to an altered transcriptome in SMCs of the C57Bl/6 aorta at an atherosclerosis-prone location. This is in agreement with findings in endothelial cells in atherosclerosis-prone regions. It could be due to biomechanical differences, for instance in wall tension or shear stress, or the different embryological origin of SMCs in AA and TA.

ORGANISM(S): Mus musculus

PROVIDER: GSE13835 | GEO | 2009/05/15

SECONDARY ACCESSION(S): PRJNA114585

REPOSITORIES: GEO

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Project description:OBJECTIVE: When aortic cells are under stress, such as increased hemodynamic pressure, they adapt to the environment by modifying their functions, allowing the aorta to maintain its strength. To understand the regulation of this adaptive response, we examined the transcriptomic and epigenomic programs in aortic smooth muscle cells (SMCs) during the adaptive response to angiotensin II (AngII) infusion and determined its importance in protecting against aortic aneurysm and dissection. APPROACH AND RESULTS: In wild-type mice, AngII infusion increased medial thickness in the thoracic aorta. Single-cell RNA sequencing analysis revealed an adaptive response in thoracic SMCs characterized by the upregulation of genes with roles in wound healing, elastin and collagen production, proliferation, migration, cytoskeleton organization, cell-matrix focal adhesion, and AKT and TGF-β signaling. Further single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) analysis showed increased chromatin accessibility at the regulatory regions of adaptive genes and revealed the mechanical sensor YAP/TEADs as a top candidate transcription complex driving the increased abundance of these gene transcripts (e.g., Lox, Col5a2 and Tgfb2). In cultured human aortic SMCs, cyclic stretch activated YAP, which directly bound to the regulatory regions of the adaptive genes (e.g., Lox) and increased the abundance of their transcripts. Finally, SMC-specific Yap deletion in mice compromised this adaptive response in SMCs, leading to an increased incidence of aortic aneurysm and dissection and a trend of increased rupture. CONCLUSIONS: Aortic stress triggers the systemic epigenetic induction of adaptive response (e.g., wound healing, proliferation, and matrix organization) in thoracic aortic SMCs, that depends on functional biomechanical signal transduction (e.g., YAP signaling). Our study highlights the importance of the adaptive response in maintaining aortic homeostasis and preventing aortic disease development in mice.

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Smooth muscle cells in atherosclerosis-prone and resistant regions of the aorta of C57Bl/6 mice at age of 4 months

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