Atherosclerosis originates as focal arterial lesions having a predictable distribution to regions of bifurcations, branches, and inner curvatures where blood flow characteristics are complex. Distinct endothelial phenotypes correlate with regional hemodynamics. We propose that systemic risk factors modify regional endothelial phenotype to influence focal susceptibility to atherosclerosis. Transcript profiles of freshly isolated endothelial cells from three atherosusceptible and three atheroprotected arterial regions in adult swine were analyzed to determine the initial prelesional effects of hypercholesterolemia on endothelial phenotypes in vivo. Cholesterol efflux transporter ATP-binding cassette transporter A1 (ABCA1) was upregulated at all sites in response to short-term high-fat diet. Proinflammatory and antioxidative endothelial gene expression profiles were induced in atherosusceptible and atheroprotected regions, respectively. However, markers for endoplasmic reticulum stress, a signature of susceptible endothelial phenotype, were not further enhanced by brief hypercholesterolemia. Both region-specific and ubiquitous (ABCA1) phenotype changes were identified as early prelesional responses of the endothelium to hypercholesterolemia. microarray; hypercholesterolemia; Oil Red O; endoplasmic reticulum stress; unfolded protein response

Endothelial cells (EC) in atherosclerosis‐prone regions of arteries display distinct gene expression profiles compared to athero‐protected regions. We investigated the differential alteration of EC phenotype at these sites during brief hypercholesterolemia. Eleven adult male swine were fed a normal chow diet (n=6) or an isocaloric high fat diet (n=5) for a period of 2 weeks. EC RNA was isolated from 3 protected (carotid, descending thoracic, renal arteries) and 3 susceptible (aortic arch, renal branch, abdominal aorta) arterial regions, linearly amplified and hybridized to porcine microarrays. Fifty eight lipid metabolism related genes were differentially expressed in ECs from all regions in response to hypercholesterolemia. However, ATP Binding Cassette A1 (ABCA1), an endothelial transmembrane protein that regulates phospholipids and cholesterol homeostasis inside the cell in response to changing levels of cholesterol in the blood, was specifically upregulated in athero‐protected regions. This response was also validated at the protein level by immunohistochemistry. Region‐specific upregulation of ABCA1 transcript and protein in ECs demonstrates a site‐specific differential EC phenotypic response to hypercholesterolemia. Supported by grants from NHLBI.