Substrate stiffness promotes vascular smooth muscle cell calcification by reducing levels of nuclear actin monomers: Mechanical regulation of VSMC calcification

Madeleine C McNeill, Frederic P L K K Li Mow Chee, Reza Ebrahimighaei, Graciela B Sala-Newby, Andrew C Newby, Tom P Hathway, Anilkumar Sankanahalli Annaiah, Shincy Joseph, Michele Carrabba, Mark Bond*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

Background:
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.

Methods:
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.

Results:
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).

Conclusion:
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.
Original languageEnglish
Pages (from-to)65-79
Number of pages15
JournalJournal of Molecular and Cellular Cardiology
Volume187
Early online date5 Jan 2024
Publication statusPublished - 1 Feb 2024

Bibliographical note

Funding Information:
This work was funded by British Heart Foundation research project number PG/20/10292.

Publisher Copyright:
© 2023 Published by Elsevier Ltd.

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