Systems biology of the functional and dysfunctional endothelium

This review provides an overview of the effect of blood flow on endothelial cell (EC) signalling pathways, applying micro-array technologies to cultured cells, and in vivo studies of normal and atherosclerotic animals. It is found that in cultured ECs, 5-10% of genes are up-or down-regulated in response to fluid flow, whereas only 3-6% of genes are regulated by varying levels of fluid flow. Of all genes, 90% are regulated by the steady part of fluid flow and 10% by pulsatile components. The associated gene profiles show high variability from experiment to experiment depending on experimental conditions, and importantly, the bioinformatical methods used to analyse the data. Despite this high variability, the current data sets can be summarized with the concept of endothelial priming. In this concept, fluid flows confer protection by an up-regulation of anti-atherogenic, anti-thrombotic, and anti-inflammatory gene signatures. Consequently, predilection sites of atherosclerosis, which are associated with low-shear stress, confer low protection for atherosclerosis and are, therefore, more sensitive to high cholesterol levels. Recent studies in intact non-atherosclerotic animals confirmed these in vitro studies, and suggest that a spatial component might be present. Despite the large variability, a few signalling pathways were consistently present in the majority of studies. These were the MAPK, the nuclear factor-kappa B, and the endothelial nitric oxide synthase-NO pathways.