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Adaptation of the endothelium to fluid flow: in vitro analyses of gene expression and in vivo implications

Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA, swasserman{at}cvmed.stanford.edu

James N Topper

Frazier Healthcare Ventures, Palo Alto, CA, USA

Biomechanical forces generated by blood flow play an important role in the pathogenesis of vascular disease. For example, regions exposed to non-uniform shear stresses develop early atherosclerotic lesions while areas exposed to uniform shear stresses are protected. A variety of in vitro flow apparatuses have been created to apply well-characterized flow patterns to endothelial cells in an effort to dissect the cellular and molecular pathways involved in these distinct processes. Recent advances in biotechnology have permitted large-scale transcriptional profiling techniques to replace candidate gene screens and have allowed the genome-wide examination of biomechanical force-induced endothelial gene expression profiles. This review provides an overview of biomechanical force-induced modulation of endothelial phenotype. It examines the effect of sustained laminar shear stress (LSS), a type of uniform shear stress, on in vitro endothelial gene expression by synthesizing data from the early candidate gene and differential display polymerase chain reaction (PCR) approaches to the numerous, recent, high throughput functional genomic analyses. These studies demonstrate that prolonged LSS regulates the expression of only a small percentage (1-5%) of endothelial genes, and this transcriptional profile produces an endothelial phenotype that is quiescent, being protected from apoptosis, inflammation and oxidative stress. These observations provide a possible molecular mechanism for the strong correlation between patterns of blood flow and the occurrence of vascular pathologies, such as atherosclerosis, in vivo.

Key Words: atherosclerosis • endothelium • gene expression • laminar shear stress • transcriptional profile

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