Non-Invasive Molecular Imaging of Shear Stress-Induced Endothelial Activation and Atherosclerotic Plaque Vulnerability

Atherosclerosis is a lipid- and inflammation driven disease of the larger arteries and is found at specific locations in the arterial tree, i.e. at branches and bends where endothelial cells are exposed to low and low, oscillatory shear stress. Shear stress, the frictional force acting on the endothelial cells as a result of the blood flow, affects endothelial physiology. It determines the location of atherosclerotic lesion development as low and low, oscillatory shear stress induce pro-inflammatory transcription factors but reduce expression and/or activity of anti-inflammatory transcription factors in endothelial cells, rendering the vascular wall vulnerable for inflammation. Consequently, in the presence of atherosclerotic risk factors, such as hypercholesterolemia and diabetes, atherosclerotic lesion development can occur. Although the relationship between low and low, oscillatory shear stress and the prevalence of atherosclerosis has been recognized for several decades, insight into the mechanisms underlying this relationship is still incomplete. The correlation between shear stress and endothelial inflammation was demonstrated by in vitro experiments, in which cultured endothelial cells were exposed to specific flow profiles, and confirmed in vivo by gene expression pattern studies at atherosclerosis-susceptible sites. However, the relationship was not substantiated by direct causal in vivo evidence. Therefore, we developed a method to change the local shear stress field in mice in vivo and studied its effect on the endothelial molecular pathways and resulting atherosclerotic plaque formation. Moreover it allowed us to develop non-invasive molecular imaging strategies to detect vulnerable plaques.