Mechanosensitive endothelial gene expression profiles: scripts for the role of hemodynamics in atherogenesis?

Abstract

The possibility that hemodynamic forces can act as a "local risk factor" for endothelial dysfunction provides a conceptual framework for the longstanding observation that the earliest lesions of atherosclerosis develop in a nonrandom pattern, the geometries of which correlate with branch points and other regions of altered blood flow. This has led us to hypothesize that hemodynamic forces, in particular wall shear stresses generated by complex patterns of blood flow, can function as both positive and negative stimuli in atherogenesis via effects on endothelial cell gene expression. To understand how endothelial cells in different regions of the arterial tree acquire both functional and dysfunctional phenotypes due to regional hemodynamics, it was important to begin to delineate, in a comprehensive fashion, the mechanoresponsiveness of endothelial cells. To address this fundamental question, we undertook high-throughput transcriptional profiling to assess the global patterns of gene expression in cultured endothelial cells exposed to two defined biomechanical stimuli. Analyses of the transcriptional activity of thousands of genes have revealed unique patterns of gene expression associated with certain types of stimuli. These unique gene expression programs and their associated functional phenotypes constitute the strongest evidence to date that vascular endothelial cells can discriminate among different types of biomechanical stimuli. The results of these studies and the working hypotheses inspired by detailed molecular analyses of biomechanically activated vascular endothelium promise to provide new insights into the role of hemodynamics in the pathogenesis of atherosclerosis.