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The role of macrophage Socs3 in the pathogenesis of aortic dissection

ABSTRACT: Background—Aortic dissection (AD) is a life-threatening medical emergency caused by the abrupt destruction of the intimomedial layer of the aortic walls. As previous studies have reported the involvement of proinflammatory cytokine IL-6 in AD pathogenesis, we investigated the role of Stat3 signaling, a downstream pathway of IL-6 in macrophages in pathogenesis of AD. Methods and Results—We characterized the pathological and molecular events triggered by aortic stress, which can lead to AD. Aortic stress on the suprarenal aorta due to infrarenal aorta stiffening and angiotensin II infusion for 1 week caused focal medial rupture at the branching point of the celiac trunk and superior mesenteric artery. This focal medial rupture in 6 weeks in wild type (WT) mice but progressed to AD in mice with macrophage-specific deletion of Socs3 gene (mSocs3-KO). mSocs3-KO mice showed premature activation of cell proliferation, an inflammatory response, and skewed differentiation of macrophages toward the tissue-destructive phenotype. Concomitantly, they showed aberrant phenotypic modulation of SMCs and TGFβ signaling, which are likely to participate in tissue repair. Human AD samples revealed STAT3 activation in adventitial macrophages adjacent to the site of tissue destruction. Conclusions—These findings suggest that AD development is preceded by focal medial rupture, in which macrophage Socs3 maintains proper inflammatory response and differentiation of SMCs, thus promoting fibrotic healing to prevent tissue destruction and AD development. Understanding the sequence of the pathological and molecular events preceding AD development will help predict and prevent AD development and progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE107479 | GEO | 2017/11/30

SECONDARY ACCESSION(S): PRJNA420217

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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The role of macrophage Socs3 in the pathogenesis of aortic dissection

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