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

Abstract

Atherosclerosis, the leading cause of death worldwide, is characterised by lipid-rich plaques within arteries, typically at low shear regions like bifurcations. Atherosclerosis is initiated by dysfunction of the inner arterial layer, the endothelium, and characterised by increased inflammation and immune cell adhesion. While statins are administered clinically to lower blood lipid levels, they also reduce endothelial dysfunction, however, the underlying mechanisms are poorly understood. Dynamic in vitro models are critical to investigate this, but current in vitro systems typically lack physiologically complex geometries and local shear changes. Here, we applied a bifurcating coronary artery-on-a-chip model of endothelial dysfunction to assess the effects of the common statin, simvastatin, on endothelial physiology. Simvastatin increased eNOS expression under healthy conditions, and reduced inflammation-induced ICAM-1 expression in high shear (12.7 dyn per cm²) regions. Importantly, for the first time, simvastatin was found to decouple ICAM-1 expression from shear. Consequently, under dysfunctional conditions, human immune cells adhered across the chip, with spatial mapping revealing preferential adhesion at the bifurcation, which was substantially reduced by pre-treatment with simvastatin. This coronary artery-on-a-chip establishes a system to spatially map functional changes in endothelial cell behaviour in response to differential shear, geometry and drug treatment, enabling future studies into plaque initiation events and treatment targets.