Extracellular Matrix Stiffness Promotes Vascular Smooth Muscle Cell Calcification By Reducing The Levels Of Nuclear Actin Monomers

Abstract

1.0ABSTRACTBackgroundVascular 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.MethodsUsing hydrogels of tuneable stiffness and lysyl oxidase-mediated stiffening of human saphenous vein ex vivo,we investigated the role of extracellular matrix (ECM) stiffness in the regulation of VSMC calcificationResultsWe demonstrate that increased ECM stiffness enhances VSMC osteogenic differentiation and VSMC calcification. We show that the effects of ECM stiffness are mediated via a reduction in the level of actin monomer within the nucleus. We show that in cells interacting with soft ECM, 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).ConclusionThis work highlights for the first time the role of nuclear actin in mediating ECM stiffness-dependent VSMC calcification and the dual role of YAP-TEAD and YAP-RUNX2 transcriptional complexes.2.0GRAPHICAL ABSTRACT9.0HIGHLIGHTSIncreased ECM stiffness promotes VSMC calcification.Increased ECM stiffness reduces levels of nuclear actin monomer.On physiological soft ECM, high levels of nuclear actin monomer inhibits calcification by repressing YAP activation.YAP activation promotes calcification by stimulating the activity of TEAD and RUNX2.