Coexisting proinflammatory and antioxidative endothelial transcription profiles in a disturbed flow region of the adult porcine aorta

• DOI: 10.1073/pnas.0305938101
• Publication Date: 2004-02-25T04:03:03Z
• Authors: Anthony G. Passerini; Denise C. Polacek; Congzhu Shi; Nadeene M. Francesco; Elisabetta Manduchi; Gregory R. Grant; William F. Pritchard; Steven Powell; Gary Y. Chang; Christian J. Stoe...; Peter F. Davies
• Keywords: Male; Transcription, Genetic; Swine; Gene Expression Profiling; Computational Biology; Proteins; Reproducibility of Results; Apoptosis; Polymerase Chain Reaction; Enzymes; 03 medical and health sciences; 0302 clinical medicine; Gene Expression Regulation; Regional Blood Flow; Animals; Endothelium, Vascular; Oxidation-Reduction; Aorta

In the arterial circulation, regions of disturbed flow (DF), which are characterized by flow separation and transient vortices, are susceptible to atherogenesis, whereas regions of undisturbed laminar flow (UF) appear protected. Coordinated regulation of gene expression by endothelial cells (EC) may result in differing regional phenotypes that either favor or inhibit atherogenesis. Linearly amplified RNA from freshly isolated EC of DF (inner aortic arch) and UF (descending thoracic aorta) regions of normal adult pigs was used to profile differential gene expression reflecting the steady statein vivo. By using human cDNA arrays, ≈2,000 putatively differentially expressed genes were identified through false-discovery-rate statistical methods. A sampling of these genes was validated by quantitative real-time PCR and/or immunostainingen face. Biological pathway analysis revealed that in DF there was up-regulation of several broad-acting inflammatory cytokines and receptors, in addition to elements of the NF-κB system, which is consistent with a proinflammatory phenotype. However, the NF-κB complex was predominantly cytoplasmic (inactive) in both regions, and no significant differences were observed in the expression of key adhesion molecules for inflammatory cells associated with early atherogenesis. Furthermore, there was no histological evidence of inflammation. Protective profiles were observed in DF regions, notably an enhanced antioxidative gene expression. This study provides a public database of regional EC gene expression in a normal animal, implicates hemodynamics as a contributory mechanism to athero-susceptibility, and reveals the coexistence of pro- and antiatherosclerotic transcript profiles in susceptible regions. The introduction of additional risk factors may shift this balance to favor lesion development.