title: Extracellular matrix presentation modulates vascular smooth muscle cell mechanotransduction.
abstract: The development of atherosclerosis involves phenotypic changes among vascular smooth muscle cells (VSMCs) that correlate with stiffening and remodeling of the extracellular matrix (ECM). VSMCs are highly sensitive to the composition and mechanical state of the surrounding ECM, and ECM remodeling during atherosclerosis likely contributes to pathology. We hypothesized that ECM mechanics and biochemistry are interdependent in their regulation of VSMC behavior and investigated the effect of ligand presentation on certain stiffness-mediated processes. Our findings demonstrate that substrate stiffening is not a unidirectional stimulus-instead, the influence of mechanics on cell behavior is highly conditioned on ligand biochemistry. This "stiffness-by-ligand" effect was evident for VSMC adhesion, spreading, cytoskeletal polymerization, and focal adhesion assembly, where VSMCs cultured on fibronectin (Fn)-modified substrates showed an augmented response to increasing stiffness, whereas cells on laminin (Ln) substrates showed a dampened response. By contrast, cells on Fn substrates showed a decrease in myosin light chain (MLC) phosphorylation and elongation with increasing stiffness, whereas Ln supported an increase in MLC phosphorylation and no change in cell shape with increasing stiffness. Taken together, these findings show that identical cell populations exhibit opposing responses to substrate stiffening depending on ECM presentation. Our results also suggest that the shift in VSMC phenotype in a developing atherosclerotic lesion is jointly regulated by stromal mechanics and biochemistry. This study highlights the complex influence of the blood vessel wall microenvironment on VSMC phenotype and provides insight into how cells may integrate ECM biochemistry and mechanics during normal and pathological tissue function.
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Sazonova
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
authors.forename: Brett C
authors.initials: BC
authors.lastname: Isenberg
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Herrmann
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Lee
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Purwada
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
authors.forename: Alex D
authors.initials: AD
authors.lastname: Valentine
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
authors.forename: Jo Ann
authors.initials: JA
authors.lastname: Buczek-Thomas
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA. Electronic address: jywong@bu.edu.
authors.forename: Joyce Y
authors.initials: JY
authors.lastname: Wong
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; Departments of Biochemistry and Ophthalmology, Boston University School of Medicine, Boston, MA 02118, USA; Department of Biological Sciences, University of Massachusetts Lowell, Lowell, MA 01854, USA. Electronic address: matthew_nugent@uml.edu.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Nugent
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001011:Aorta / Q000166:cytology* / Q000502:physiology; D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000502:physiology*; D040542:Mechanotransduction, Cellular; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology*; D018994:Myosin Light Chains / Q000378:metabolism; D051381:Rats
chemical_list: D018994:Myosin Light Chains
keywords: Atherosclerosis; Contraction; Fibronectin; Laminin; Substrate stiffness