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Articles in PresS, published online ahead of print February 19, 2002
Physiol Genomics, 10.1152/physiolgenomics.00075.2001
Submitted on August 29, 2001
Accepted on February 14, 2002
1 Gene Therapy, Berlex Biosciences, Richmond, CA, USA
* To whom correspondence should be addressed. E-mail: alan_brooks{at}berlex.com.
Subtraction cloning and cDNA arrays were used to compare steady state mRNA levels in cultured human aortic endothelial cells (HAEC) exposed for up to 24 h to either high shear (13 dynes/cm2) steady laminar flow (LF), an established representation of "atheroprotective" flow conditions, or low shear (<1 dyne/cm2), pulsatile, non-steady, non-unidireactional flow (disturbed flow, DF) that simulates conditions in the atherosclerosis-prone areas of the arterial circulation. More than 100 genes not previously known to be flow regulated were identified. Analysis of selected genes by quantitative RT-PCR confirmed the results obtained from the microarrays. These data demonstrate that DF is not simply the absence of LF but in fact represents a distinct bio-mechanical stimulus that has a profound impact upon the gene expression profile of human aortic EC in culture. In line with previous studies, many of the changes in mRNA levels induced by LF are athero-protective. In contrast, DF up-regulated the mRNA levels of a plethora of pro-atherosclerotic genes including pro-inflammatory, pro-apoptotic, and pro-coagulant molecules. For some of the genes whose expression was altered by DF and LF, corresponding changes in EC function (proliferation and monocyte adhesion) could be demonstrated. Specifically, the sustained up-regulation of VCAM-1 and increased monocyte adhesion to EC exposed to DF was similar to that found in EC in vivo at atherosclerosis prone regions, confirming the relevance of our model system for in vivo conditions. Distinct differences in the cellular response induced by TNF
and DF suggest that the effects of DF are not mediated entirely by the same signaling pathways that activate NF-
B. These studies demonstrate extensive and pathophysiologically relevant changes in sustained gene expression patterns in aortic EC exposed to DF compared to LF which are predicted to induce a pro-atherogenic EC phenotype.
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