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Clearance of Stress-Induced Premature Senescent Cells Alleviates the Formation of Abdominal Aortic Aneurysms.

ABSTRACT: Abdominal aortic aneurysm (AAA) is a multifactorial disease characterized by various pathophysiological processes, including chronic inflammation, oxidative stress, and proteolytic activity in the aortic wall. Stress-induced premature senescence (SIPS) has been implicated in regulating these pathophysiological processes, but whether SIPS contributes to AAA formation remains unknown. Here, we detected SIPS in AAA from patients and young mice. The senolytic agent ABT263 prevented AAA development by inhibiting SIPS. Additionally, SIPS promoted the transformation of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a synthetic phenotype, whereas inhibition of SIPS by the senolytic drug ABT263 suppressed VSMC phenotypic switching. RNA sequencing and single-cell RNA sequencing analysis revealed that fibroblast growth factor 9 (FGF9), secreted by stress-induced premature senescent VSMCs, was a key regulator of VSMC phenotypic switching and that FGF9 knockdown abolished this effect. We further showed that the FGF9 level was critical for the activation of PDGFRβ/ERK1/2 signaling, facilitating VSMC phenotypic change. Taken together, our findings demonstrated that SIPS is critical for VSMC phenotypic switching through the activation of FGF9/PDGFRβ/ERK1/2 signaling, promoting AAA development and progression. Thus, targeting SIPS with the senolytic agent ABT263 may be a valuable therapeutic strategy for the prevention or treatment of AAA.

SUBMITTER: Xie J

PROVIDER: S-EPMC10529745 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Clearance of Stress-Induced Premature Senescent Cells Alleviates the Formation of Abdominal Aortic Aneurysms.

Xie Jingfang J Tang Zhenquan Z Chen Qiqi Q Jia Xiaoqian X Li Chuling C Jin Ming M Wei Guoquan G Zheng Hao H Li Xinzhong X Chen Yanmei Y Liao Wangjun W Liao Yulin Y Bin Jianping J Huang Senlin S

Aging and disease 20231001 5

Abdominal aortic aneurysm (AAA) is a multifactorial disease characterized by various pathophysiological processes, including chronic inflammation, oxidative stress, and proteolytic activity in the aortic wall. Stress-induced premature senescence (SIPS) has been implicated in regulating these pathophysiological processes, but whether SIPS contributes to AAA formation remains unknown. Here, we detected SIPS in AAA from patients and young mice. The senolytic agent ABT263 prevented AAA development b ...[more]

PMID: 37196124

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Project description:Abdominal aortic aneurysm (AAA) is a vascular disease characterized by the enlargement of the infrarenal segment of the aorta. A ruptured AAA can cause internal bleeding and carries a high mortality rate, which is why the clinical management of the disease is focused on preventing aneurysm rupture. AAA rupture risk is estimated by the change in maximum diameter over time (i.e., growth rate) or if the diameter reaches a prescribed threshold. The latter is typically 5.5 cm in most clinical centers, at which time surgical intervention is recommended. While a size-based criterion is suitable for most patients who are diagnosed at an early stage of the disease, it is well known that some small AAA rupture or patients become symptomatic prior to a maximum diameter of 5.5 cm. Consequently, the mechanical stress in the aortic wall can also be used as an integral component of a biomechanics-based rupture risk assessment strategy. In this work, we seek to identify geometric characteristics that correlate strongly with wall stress using a sample space of 100 asymptomatic, unruptured, electively repaired AAA models. The segmentation of the clinical images, volume meshing, and quantification of up to 45 geometric measures of each AAA were done using in-house Matlab scripts. Finite element analysis was performed to compute the first principal stress distributions from which three global biomechanical parameters were calculated: peak wall stress, 99th percentile wall stress and spatially averaged wall stress. Following a feature reduction approach consisting of Pearson's correlation matrices with Bonferroni correction and linear regressions, a multivariate stepwise regression analysis was conducted to find the geometric measures most highly correlated with each of the biomechanical parameters. Our findings indicate that wall stress can be predicted by geometric indices with an accuracy of up to 94% when AAA models are generated with uniform wall thickness and up to 67% for patient specific, non-uniform wall thickness AAA. These geometric predictors of wall stress could be used in lieu of complex finite element models as part of a geometry-based protocol for rupture risk assessment.

Dataset Information

Clearance of Stress-Induced Premature Senescent Cells Alleviates the Formation of Abdominal Aortic Aneurysms.

Publications

Clearance of Stress-Induced Premature Senescent Cells Alleviates the Formation of Abdominal Aortic Aneurysms.

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