Unidirectional and oscillatory shear stress differentially modulate NOS III gene expression

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Biomedical Engineering

Background:

• Atherosclerotic plaques form in areas of low shear stress and oscillatory blood flow.
• Endothelial cells in plaque-prone regions exhibit different gene expression patterns compared to plaque-free zones.
• Previous studies indicated differential regulation of endothelial nitric oxide synthase (NOS III) gene expression by flow patterns.

Purpose of the Study:

• To investigate the mechanisms underlying the selective unresponsiveness of NOS III gene regulation to oscillatory flow.
• To elucidate the role of signaling pathways and cis-acting elements in flow-mediated gene expression.

Main Methods:

• Utilized a unique experimental flow system to expose endothelial cells to unidirectional and oscillatory shear stress.
• Analyzed the 1600-base-pair NOS III gene promoter activity.
• Investigated the involvement of NF-kappaB and Ras-dependent MAP kinase pathways.
• Identified potential cis-acting regulatory elements within the NOS III gene.

Main Results:

• Both unidirectional and oscillatory shear stress induced NOS III gene promoter activity via NF-kappaB activation.
• Ras-dependent MAP kinase activation was not involved in NOS III gene induction by either flow pattern.
• Oscillatory flow failed to induce NOS III gene regulation, suggesting the presence of a negative regulatory mechanism.

Conclusions:

• NOS III gene promoter induction by shear stress involves NF-kappaB but not Ras-MAPK pathways.
• A novel, unidentified negative cis-acting element in the NOS III gene is responsible for the lack of induction under oscillatory flow conditions.
• Understanding these mechanisms could provide insights into preventing atherosclerosis development in specific vascular regions.