Higher matrix stiffness promotes VSMC senescence by affecting mitochondria–ER contact sites and mitochondria/ER dysfunction

Abstract

Abdominal aortic aneurysm (AAA) is a prevalent condition characterized by the weakening and bulging of the abdominal aorta. This study aimed to investigate the impact of a stiff matrix on vascular smooth muscle cells (VSMCs) in AAA development. Bioinformatics analysis revealed that differentially expressed genes (DEGs) in VSMCs of an AAA mouse model were enriched in cellular senescence and related pathways. To simulate aging‐related changes, VSMCs were cultured on stiff matrices, and compared to those on soft matrices, the VSMCs cultured on stiff matrices exhibited cellular senescence. Furthermore, the mutual distance between mitochondria and endoplasmic reticulum (ER) in VSMCs was increased, indicating altered mitochondria–endoplasmic reticulum contacts (MERCs). The observed upregulation of reactive oxygen species (ROS) levels, antioxidant gene expression, and decreased mitochondrial membrane potential suggested the presence of mitochondrial dysfunction in VSMCs cultured on a stiff matrix. Additionally, the induction of ER stress‐related genes indicated ER dysfunction. These findings collectively indicated impaired functionality of both mitochondria and ER in VSMCs cultured on a stiff matrix. Moreover, our data revealed that high lipid levels exacerbated the effects of high matrix stiffness on VSMCs senescence, MERC sites, and mitochondria/ER dysfunction. Importantly, treatment with the antilipemic agent CI‐981 effectively reversed these detrimental effects. These findings provide insights into the role of matrix stiffness, mitochondrial dysfunction, ER stress, and lipid metabolism in AAA development, suggesting potential therapeutic targets for intervention.

Involvement of Matricellular Proteins in Cellular Senescence: Potential Therapeutic Targets for Age-Related Diseases

“…Changes in mechanical properties, the increase in ECM, and tissue stiffness contribute to disease development and progression [ 195 , 196 , 197 , 198 ]. Notably, many studies have demonstrated that tissue stiffening enhances integrin signaling [ 199 , 200 ], and increasing evidence on enhanced ECM stiffness-induced cellular senescence has provided important insights into the pathogenesis of age-related diseases, including OA, abdominal aortic aneurysm, and IDD [ 34 , 201 , 202 , 203 , 204 , 205 ]. Wang and colleagues recently found that the increased stiffness of human NP tissue specimens with IDD is correlated with an increase in the degeneration grade [ 203 ].…”

The Research on Deep Learning-Driven Dimensionality Reduction and Strain Prediction Techniques Based on Flight Parameter Data

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