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(American Journal of Pathology. 2007;171:1691-1704.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060860

Relative Reduction of Endothelial Nitric-Oxide Synthase Expression and Transcription in Atherosclerosis-Prone Regions of the Mouse Aorta and in an in Vitro Model of Disturbed Flow

Doyon Won^*, Su-Ning Zhu^*, Mian Chen^*, Anouk-Martine Teichert, Jason E. Fish^*, Charles C. Matouk, Michael Bonert, Matadial Ojha^¶, Philip A. Marsden^* and Myron I. Cybulsky^*

From the Departments of Laboratory Medicine and Pathobiology^* and Medicine, and the Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario; the Toronto General Research Institute, Toronto, Ontario; and the Department of Surgery,^¶ University Health Network, Toronto, Ontario, Canada

Atherosclerosis develops in distinct regions of the arterial tree. Defining patterns and mechanisms of endothelial cell gene expression in different regions of normal arteries is key to understanding the initial molecular events in atherogenesis. In this study, we demonstrated that the expression of endothelial nitric-oxide synthase (eNOS), an atheroprotective gene, and its phosphorylation on Ser¹¹⁷⁷, a marker of activity, were lower in regions of the normal mouse aorta that are predisposed to atherosclerosis. The same expression pattern was observed in mouse strains that are both susceptible and resistant to atherosclerosis, and the topography of eNOS expression was inverse to p65, the main nuclear factor-B subunit. Modeling of disturbed and uniform laminar flow in vitro reproduced the expression patterns of eNOS and p65 that were found in vivo. Heterogeneous nuclear RNA expression and RNA polymerase II chromosome immunoprecipitation studies demonstrated that regulation of transcription contributed to increased eNOS expression in response to shear stress. In vivo, the transcription of eNOS was reduced in regions of the mouse aorta predisposed to atherosclerosis, as defined by reporter gene expression in eNOS promoter-ß-galactosidase reporter transgenic mice. These data suggest that disturbed hemodynamic patterns found at arterial branches and curvatures uniquely modulate endothelial cell gene expression by regulating transcription, potentially explaining why these regions preferentially develop atherosclerosis when risk factors such as hypercholesterolemia are introduced.

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