Substrate stiffness promotes vascular smooth muscle cell calcification by reducing the levels of nuclear actin monomers

Vascular calcification (VC) is a prevalent independent risk factor for adverse cardiovascular events and is associated with diabetes, hypertension, chronic kidney disease, and atherosclerosis. However, the mechanisms regulating the osteogenic differentiation of vascular smooth muscle cells (VSMC) ar...

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Bibliographic Details
Published in:Journal of molecular and cellular cardiology 2024-02, Vol.187, p.65-79
Main Authors: McNeill, M.C., Li Mow Chee, F., Ebrahimighaei, R., Sala-Newby, G.B., Newby, A.C., Hathway, T., Annaiah, A.S., Joseph, S., Carrabba, M., Bond, M.
Format: Article
Language:English
Subjects:
Actins
Calcification
Cells, Cultured
Core Binding Factor Alpha 1 Subunit - genetics
Extracellular matrix
Humans
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Osteogenesis
RUNX2
Stiffening
TEAD
Vascular Calcification
Vascular smooth muscle cell
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Summary:Vascular calcification (VC) is a prevalent independent risk factor for adverse cardiovascular events and is associated with diabetes, hypertension, chronic kidney disease, and atherosclerosis. However, the mechanisms regulating the osteogenic differentiation of vascular smooth muscle cells (VSMC) are not fully understood. Using hydrogels of tuneable stiffness and lysyl oxidase-mediated stiffening of human saphenous vein ex vivo, we investigated the role of substrate stiffness in the regulation of VSMC calcification. We demonstrate that increased substrate stiffness enhances VSMC osteogenic differentiation and VSMC calcification. We show that the effects of substrate stiffness are mediated via a reduction in the level of actin monomer within the nucleus. We show that in cells interacting with soft substrate, elevated levels of nuclear actin monomer repress osteogenic differentiation and calcification by repressing YAP-mediated activation of both TEA Domain transcription factor (TEAD) and RUNX Family Transcription factor 2 (RUNX2). This work highlights for the first time the role of nuclear actin in mediating substrate stiffness-dependent VSMC calcification and the dual role of YAP-TEAD and YAP-RUNX2 transcriptional complexes. [Display omitted] •Increased substrate stiffness promotes VSMC calcification.•Increased substrate stiffness reduces levels of nuclear actin monomer.•On physiological soft substrates, high levels of nuclear actin monomer inhibit calcification by repressing YAP activation.•YAP activation promotes calcification by stimulating the activity of TEAD and RUNX2.
ISSN:0022-2828
1095-8584
DOI:10.1016/j.yjmcc.2023.12.005