Regional arterial hemodynamics correlates with distinct endothelial phenotypes that may be modified by risk factors to influence focal and regional susceptibility to atherosclerosis. We compared endothelial transcript profiles from hemodynamically distinct arterial regions in 15 mature pigs: males and females fed a normal diet, and males fed a high-fat diet (15 % lard, 1.5 % cholesterol) for two weeks. Hierarchical clustering analysis showed preferential grouping of arrays by region over risk factor. A set of differentially expressed genes was identified which clearly distinguished regions of disturbed flow from undisturbed flow; however, few differences were observed within the same region based on gender or diet. Consistent with previous results in the absence of risk factors, the balance in gene expression was not inherently pathological at this early time-point. The results implicate regional hemodynamics as a predominant epigenetic determinant of endothelial phenotypic heterogeneity underlying atherosusceptibility in vivo. (c) 2005 Elsevier Inc. All rights reserved.