Sox9 Accelerates Vascular Aging by Regulating Extracellular Matrix Composition and Stiffness.

Area of Science:

• Vascular Biology
• Cellular Aging
• Biomaterials Science

Background:

• Vascular calcification and increased extracellular matrix (ECM) stiffness are key features of vascular aging.
• Sox9 (SRY-box transcription factor 9) is linked to vascular smooth muscle cell (VSMC) osteo/chondrogenic conversion, but its role in aging and calcification is unknown.

Purpose of the Study:

• To investigate the relationship between Sox9, vascular aging, and ECM properties.
• To elucidate the role of Sox9 in regulating VSMC phenotype and ECM characteristics during aging.

Main Methods:

• Immunohistochemistry on human aortic samples from young and aged patients.
• In vitro studies using young and senescent VSMCs, manipulating Sox9 expression.
• Characterization of ECM properties using atomic force microscopy and proteomics.
• Assessment of VSMC phenotype on engineered matrices.

Main Results:

• Sox9 correlated with the senescence marker p16 in vivo and showed mechanosensitive expression in senescent cells and stiff matrices in vitro.
• Sox9 regulated ECM stiffness and organization by altering collagen expression and reducing VSMC contractility.
• Sox9 targeted LH3 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3), a key regulator of ECM stiffness, and promoted its deposition via extracellular vesicles.

Conclusions:

• Sox9 plays a crucial role in regulating ECM structure and composition, influencing VSMC phenotype.
• A positive feedback loop exists where senescence and ECM stiffening promote Sox9, which further enhances stiffening and senescence.
• Findings highlight the importance of ECM in regulating VSMC phenotype and suggest therapeutic targets for vascular aging.