Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption

Area of Science:

• Cardiovascular biology
• Cellular mechanics
• Pharmacology

Background:

• Arterial stiffening is associated with aging and atherosclerosis.
• Age-related arterial stiffening increases RhoA activity, cell contractility, and endothelial permeability.

Purpose of the Study:

• To investigate if simvastatin can attenuate RhoA activity and mitigate age-related arterial stiffening effects on endothelial barrier function.
• To explore simvastatin's impact on endothelial cell response to matrix stiffness.

Main Methods:

• Endothelial cells cultured on polyacrylamide gels of varying stiffness (2.5, 5, 10 kPa).
• Treatment with simvastatin.
• Assessed RhoA activity, phosphorylated myosin light chain, cell contractility, cell-cell junction size, intercellular tension, and monolayer permeability.

Main Results:

• RhoA and phosphorylated myosin light chain activity increased with matrix stiffness but decreased with simvastatin treatment.
• Simvastatin reduced cell contractility, cell-cell junction size, and intercellular tension.
• Simvastatin treatment decreased matrix stiffness-dependent increases in monolayer permeability.
• Simvastatin increased activated Rac1 levels, promoting cytoskeletal reorganization and barrier enhancement.

Conclusions:

• Simvastatin alters endothelial cell response to increased matrix stiffness, restoring barrier function.
• Simvastatin presents a potential therapeutic intervention against atherogenesis initiated by age-related arterial stiffening.