Sox9 Accelerates Vascular Aging by Regulating Extracellular Matrix Composition and Stiffness

Author:

Faleeva Maria1ORCID,Ahmad Sadia1ORCID,Theofilatos Konstantinos1ORCID,Lynham Steven2ORCID,Watson Gabriel1ORCID,Whitehead Meredith1ORCID,Marhuenda Emilie3ORCID,Iskratsch Thomas3ORCID,Cox Susan4ORCID,Shanahan Catherine M.1ORCID

Affiliation:

1. British Heart Foundation (BHF) Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences (M.F., S.A., K.T., G.W., M.W., C.M.S.) King’s College London, United Kingdom.

2. Proteomics Facility, Centre of Excellence for Mass Spectrometry (S.L.) King’s College London, United Kingdom.

3. School of Engineering and Material Science, Queen Mary University of London, United Kingdom (E.M., T.I.).

4. Randall Centre for Cell & Molecular Biophysics, Faculty of Life Sciences & Medicine (S.C.) King’s College London, United Kingdom.

Abstract

BACKGROUND: Vascular calcification and increased extracellular matrix (ECM) stiffness are hallmarks of vascular aging. Sox9 (SRY-box transcription factor 9) has been implicated in vascular smooth muscle cell (VSMC) osteo/chondrogenic conversion; however, its relationship with aging and calcification has not been studied. METHODS: Immunohistochemistry was performed on human aortic samples from young and aged patients. Young and senescent primary human VSMCs were induced to produce ECM, and Sox9 expression was manipulated using adenoviral overexpression and depletion. ECM properties were characterized using atomic force microscopy and proteomics, and VSMC phenotype on hydrogels and the ECM were examined using confocal microscopy. RESULTS: In vivo, Sox9 was not spatially associated with vascular calcification but correlated with the senescence marker p16 (cyclin-dependent kinase inhibitor 2A). In vitro Sox9 showed mechanosensitive responses with increased expression and nuclear translocation in senescent cells and on stiff matrices. Sox9 was found to regulate ECM stiffness and organization by orchestrating changes in collagen (Col) expression and reducing VSMC contractility, leading to the formation of an ECM that mirrored that of senescent cells. These ECM changes promoted phenotypic modulation of VSMCs, whereby senescent cells plated on ECM synthesized from cells depleted of Sox9 returned to a proliferative state, while proliferating cells on a matrix produced by Sox9 expressing cells showed reduced proliferation and increased DNA damage, reiterating features of senescent cells. LH3 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3) was identified as an Sox9 target and key regulator of ECM stiffness. LH3 is packaged into extracellular vesicles and Sox9 promotes extracellular vesicle secretion, leading to increased LH3 deposition within the ECM. CONCLUSIONS: These findings highlight the crucial role of ECM structure and composition in regulating VSMC phenotype. We identify a positive feedback cycle, whereby cellular senescence and increased ECM stiffening promote Sox9 expression, which, in turn, drives further ECM modifications to further accelerate stiffening and senescence.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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