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 AngII (angiotensin II) infusion and determined its importance in protecting against aortic aneurysm and dissection (AAD). Methods: We performed single-cell RNA sequencing 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 (yes-associated protein) 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. Single-cell RNA sequencing 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 PI3K-PKB/Akt (phosphoinositide-3-kinase-protein kinase B/Akt) and TGF-β (transforming growth factor beta) signaling. ScATAC-seq analysis showed increased chromatin accessibility at regulatory regions of adaptive genes and revealed the mechanical sensor YAP/transcriptional enhanced associate domains as a top candidate transcription complex driving the expression of these genes (eg, Lox, Col5a2, Tgfb2). In cultured human aortic SMCs, cyclic stretch activated YAP, which directly bound to adaptive gene regulatory regions (eg, 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 (eg, wound healing, proliferation, matrix organization) in thoracic aortic SMCs that depends on functional biomechanical signal transduction (eg, YAP signaling). Our study highlights the importance of the adaptive response in maintaining aortic homeostasis and preventing AAD in mice.
|Number of pages||19|
|Journal||Arteriosclerosis, Thrombosis, and Vascular Biology|
|State||Published - Feb 1 2023|
Bibliographical noteFunding Information:
This work was supported by NIH grants R01HL131980, R01HL143359, R01HL158157, R01 HL159988, R35HL155649 and American Heart Association grant 18SFRN33960114. Transcriptome analyses were performed at the Department of Molecular and Human Genetics Functional Genomics Core and Single Cell Genomics Core at Baylor College of Medicine, which are partially supported by grants from the NIH (grants S10OD023469, S10OD018033, S10OD025240, CA125123, and 1P30ES030285) and the Cancer Prevention Research Institute of Texas (core grant RP170005). Y. Li is supported by the Victor A. McKusick Fellowship Grant from The Marfan Foundation. S.A. LeMaire’s work is supported in part by the Jimmy and Roberta Howell Professorship in Cardiovascular Surgery at Baylor College of Medicine.
© 2023 American Heart Association, Inc.
- aortic aneurysm
- extracellular matrix
- mechanical stress
- smooth muscle cell
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine