title: Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption.
abstract: Arterial stiffening accompanies both aging and atherosclerosis, and age-related stiffening of the arterial intima increases RhoA activity and cell contractility contributing to increased endothelium permeability. Notably, statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors whose pleiotropic effects include disrupting small GTPase activity; therefore, we hypothesized the statin simvastatin could be used to attenuate RhoA activity and inhibit the deleterious effects of increased age-related matrix stiffness on endothelial barrier function. Using polyacrylamide gels with stiffnesses of 2.5, 5, and 10 kPa to mimic the physiological stiffness of young and aged arteries, endothelial cells were grown to confluence and treated with simvastatin. Our data indicate that RhoA and phosphorylated myosin light chain activity increase with matrix stiffness but are attenuated when treated with the statin. Increases in cell contractility, cell-cell junction size, and indirect measurements of intercellular tension that increase with matrix stiffness, and are correlated with matrix stiffness-dependent increases in monolayer permeability, also decrease with statin treatment. Furthermore, we report that simvastatin increases activated Rac1 levels that contribute to endothelial barrier enhancing cytoskeletal reorganization. Simvastatin, which is prescribed clinically due to its ability to lower cholesterol, alters the endothelial cell response to increased matrix stiffness to restore endothelial monolayer barrier function, and therefore, presents a possible therapeutic intervention to prevent atherogenesis initiated by age-related arterial stiffening.
authors.affiliation: Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States of America.
authors.forename: Marsha C
authors.initials: MC
authors.lastname: Lampi
authors.affiliation: Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States of America.
authors.forename: Courtney J
authors.initials: CJ
authors.lastname: Faber
authors.affiliation: Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Huynh
authors.affiliation: Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States of America.
authors.forename: Francois
authors.initials: F
authors.lastname: Bordeleau
authors.affiliation: Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States of America.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Zanotelli
authors.affiliation: Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States of America.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Reinhart-King
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects; D003599:Cytoskeleton / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007365:Intercellular Junctions / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D059289:Vascular Stiffness / Q000187:drug effects*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein