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Effects Of Simvastatin On Endothelial Cell Contractility And Barrier Integrity

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Abstract

Cardiovascular diseases are the leading cause of death in the United States. Atherosclerosis, a cardiovascular disease, can lead to stroke and heart failure, affecting 50% of the U.S. population over the age of 651. One of the first steps in the progression of atherosclerosis is increased endothelium permeability, ultimately resulting in the accumulation of lipids and formation of plaque. It has been shown that increased substrate stiffness, mimicking the stiffening that occurs naturally with age, results in increased cell contractility, cell -cell junction width, and endothelium permeability via Rho mediated contractility 2. To date therapeutics to reverse increased vascular stiffness, and in turn prevent endothelial cell dysfunction leading to increased endothelium permeability, have been limited and unsuccessful. Previous findings suggest that statins may be beneficial beyond lowering cholesterol levels by having a positive effect on endothelium integrity through the inhibition of RhoA in the actomyosin contractility pathway Rho mediated contractility 2 3-5 . As increased stiffness leads to increased permeability via and statins have been shown to decrease RhoA activity, this investigation examined the effect of simvastatin (Zocor®), a common statin, on endothelial cell morphology, cell traction forces, cell-cell junction widths, and endothelium permeability for endothelial cells seeded on 2.5, 5, and 10 kPa polyacrylamide substrates, mimicking the stiffness of healthy and aged vessels respectively. Our data show that simvastatin results in an elongated cell morphology, reduced endothelial cell contractility, enhanced cell-cell junction integrity, and decreased substratestiffness-dependent and thrombin-dependent increased endothelium permeability on physiologically relevant substrate stiffnesses. Our data suggest that simvastatin may be beneficial in preventing atherosclerosis beyond its traditional lipid lowering effects b y decreasing monolayer permeability due to vascular stiffening that naturally occurs with aging.

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2013-05-26

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King, Cynthia A.

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Butcher, Jonathan T.

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Biomedical Engineering

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M.S., Biomedical Engineering

Degree Level

Master of Science

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dissertation or thesis

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