Endothelial phenotype heterogeneity plays an important role in the susceptibility of the cardiovascular system to pathogenesis. Arteries (and heart valves) are susceptible to chronic inflammatory disease in regions of blood flow disturbance, implicating hemodynamic forces and transport characteristics as prominent influences upon pro-pathological endothelial phenotype. Our studies are focused on the normal and hypercholesterolemic domestic swine (Sus scrofa), an animal model close to human physiology and pathology, and are complemented by mechanistic in vitro studies of human arterial endothelial cells. All animal procedures were conducted under FDA and University of Pennsylvania IACUC approved protocols Microarrays and next generation sequencing combined with systems analyses were used to identify differential expression of genes, small regulatory RNAs and epigenetic modifications in atherosusceptible endothelium. Data obtained from such high throughput ‘omics’ (discovery science) measurements in cells freshly harvested from the in vivo environment ‘informed’ the design of in vitro experiments (reductionist science). Where possible, the robustness of new mechanisms discovered in vitro was further tested in vivo to complete a cycle. The association of chronic low level endoplasmic reticulum (ER) stress in endothelium in regions of flow disturbance was identified in atherosusceptible sites of aorta, carotid, renal, and coronary arteries as an important adaptive biomarker of susceptible phenotype. ER stress is linked to proinflammatory and oxidative stress pathways. Examples of microRNA and transcription factor mechanisms involved in site specific endothelial phenotype heterogeneity and pro-inflammatory/susceptible status in vivo will be presented. We propose endothelial atherosusceptibility as a systems imbalance of multiple interrelated pathways that sensitizes the cells to pathological change. However, by adjusting the balance of cellular pathways the endothelium may respond to risk factor perturbation with surprisingly protective as well as pathological outcomes, reflecting the resilient nature of endothelial adaptation to the physical and chemical environment. Research supported by the National Heart Lung and Blood Institute of the US National institutes of Health and the American Heart Association.