Dataset Information

Genetic Deletion of Socs3 in Smooth Muscle Cells Ameliorates Aortic Dissection in Mice.

ABSTRACT: Aortic dissection (AD) is the acute destruction of aortic wall and is reportedly induced by inflammatory response. Here we investigated the role of smooth muscle Socs3 (a negative regulator of Janus kinases/signal transducer and activator of transcription signaling) in AD pathogenesis using a mouse model generated via ?-aminopropionitrile and angiotensin II infusion. Socs3 deletion specifically in smooth muscle cells yielded a chronic inflammatory response of the aortic wall, which was associated with increased fibroblasts, reinforced aortic tensile strength, and less-severe tissue destruction. Although an acute inflammatory response is detrimental in AD, smooth muscle-regulated inflammatory response seemed protective against AD.

SUBMITTER: Hirakata S

PROVIDER: S-EPMC7046542 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Genetic Deletion of Socs3 in Smooth Muscle Cells Ameliorates Aortic Dissection in Mice.

Hirakata Saki S Aoki Hiroki H Ohno-Urabe Satoko S Nishihara Michihide M Furusho Aya A Nishida Norifumi N Ito Sohei S Hayashi Makiko M Yasukawa Hideo H Imaizumi Tsutomu T Hiromatsu Sinichi S Tanaka Hiroyuki H Fukumoto Yoshihiro Y

JACC. Basic to translational science 20200108 2

Aortic dissection (AD) is the acute destruction of aortic wall and is reportedly induced by inflammatory response. Here we investigated the role of smooth muscle Socs3 (a negative regulator of Janus kinases/signal transducer and activator of transcription signaling) in AD pathogenesis using a mouse model generated via β-aminopropionitrile and angiotensin II infusion. <i>Socs3</i> deletion specifically in smooth muscle cells yielded a chronic inflammatory response of the aortic wall, which was as ...[more]

PMID: 32140621

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Project description:BackgroundWhen 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).MethodsWe 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.ResultsIn 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.ConclusionsAortic 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.

Dataset Information

Genetic Deletion of Socs3 in Smooth Muscle Cells Ameliorates Aortic Dissection in Mice.

Publications

Genetic Deletion of Socs3 in Smooth Muscle Cells Ameliorates Aortic Dissection in Mice.

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