Publication Date
2-1-2023
Journal
Arteriosclerosis, Thrombosis, and Vascular Biology
DOI
10.1161/ATVBAHA.122.318135
PMID
36579645
PMCID
PMC9877188
PubMedCentral® Posted Date
2-1-2024
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Mice, Animals, Humans, Aorta, Thoracic, Proto-Oncogene Proteins c-akt, Mice, Knockout, Aorta, Aneurysm, Aortic Dissection, Collagen, Transforming Growth Factor beta, Myocytes, Smooth Muscle, Chromatin, Aortic Aneurysm, Thoracic, Cells, Cultured, Mice, Inbred C57BL, aortic aneurysm and dissection, biomechanical environment, extracellular matrix, smooth muscle cell
Abstract
BACKGROUND:
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 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 (AAD).
METHODS:
We performed single-cell RNA sequencing (scRNA-seq) and single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) analyses in a mouse model of sporadic AAD induced by AngII infusion. We also examined the direct effects of YAP on the SMC adaptive response in vitro. The role of YAP in AAD development was further evaluated in AngII-infused mice with SMC-specific Yap deletion.
RESULTS:
In wild-type mice, AngII infusion increased medial thickness in the thoracic aorta. ScRNA-seq analysis revealed an adaptive response in thoracic SMCs characterized by upregulated genes with roles in wound healing, elastin and collagen production, proliferation, migration, cytoskeleton organization, cell-matrix focal adhesion, and AKT and TGF-β signaling. ScATAC-seq analysis showed increased chromatin accessibility at regulatory regions of adaptive genes and revealed the mechanical sensor YAP/TEADs as a top candidate transcription complex driving the expression of these genes (e.g., Lox, Col5a2, Tgfb2). In cultured human aortic SMCs, cyclic stretch activated YAP, which directly bound to adaptive gene regulatory regions (e.g., Lox) and increased their transcript abundance. SMC-specific Yap deletion in mice compromised this adaptive response in SMCs, leading to an increased AAD incidence.
CONCLUSIONS:
Aortic stress triggers the systemic epigenetic induction of an adaptive response (e.g., wound healing, proliferation, 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 AAD in mice.
Graphical Abstract
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