Simvastatin attenuates endothelial dysfunction in a coronary artery-on-a-chip.

Area of Science:

• Cardiovascular Biology
• Biomedical Engineering
• Pharmacology

Background:

• Atherosclerosis, a major cause of death, involves arterial plaque buildup initiated by endothelial dysfunction and inflammation.
• Statins lower lipids and reduce endothelial dysfunction, but their precise mechanisms remain unclear.
• Existing in vitro models lack the complex geometries and shear variations found in arteries.

Purpose of the Study:

• To investigate the effects of simvastatin on endothelial physiology using a dynamic, bifurcating coronary artery-on-a-chip model.
• To assess simvastatin's impact on endothelial dysfunction, inflammation, and immune cell adhesion under varying shear conditions.
• To explore how simvastatin affects the relationship between shear stress and ICAM-1 expression.

Main Methods:

• Developed and utilized a bifurcating coronary artery-on-a-chip model mimicking physiological geometry and shear stress.
• Applied simvastatin to the chip under healthy and inflammation-induced dysfunctional conditions.
• Spatially mapped endothelial cell responses, including eNOS and ICAM-1 expression, and human immune cell adhesion.

Main Results:

• Simvastatin increased eNOS expression in healthy conditions and reduced inflammation-induced ICAM-1 expression in high shear regions.
• Crucially, simvastatin decoupled ICAM-1 expression from shear stress, a novel finding.
• Simvastatin pre-treatment significantly reduced immune cell adhesion, particularly at the arterial bifurcation under dysfunctional conditions.

Conclusions:

• The coronary artery-on-a-chip model effectively captures spatial changes in endothelial function influenced by shear, geometry, and drugs.
• Simvastatin demonstrates protective effects by modulating endothelial responses and reducing immune cell recruitment.
• This model provides a platform for future research into atherosclerosis initiation and the development of targeted therapies.