Asynchronous shear stress and circumferential strain reduces endothelial NO synthase and cyclooxygenase-2 but induces endothelin-1 gene expression in endothelial cells

Objective - Endothelium-derived vasoactive agents NO, endothelin-1 (ET-1), and prostacyclin (PGI(2)) not only regulate vascular tone but also influence atherogenic processes, including smooth muscle migration and proliferation, as well as monocyte and platelet adhesion. Complex hemodynamics characterized by the temporal phase angle between mechanical factors circumferential strain and wall shear stress ( stress phase angle [ SPA]) have been implicated in regions prone to pathologic development, such as atherosclerosis and intimal hyperplasia, in coronary and peripheral arteries where the mechanical forces are highly asynchronous (SPA = - 180degrees). We determined the gene expression of endothelial NO synthase ( eNOS), ET-1, and cyclooxygenase-2 (COX-2) affected by asynchronous hemodynamics (SPA = - 180degrees) relative to normal hemodynamics ( SPA = 0degrees) in bovine aortic endothelial cells. Methods and Results - Quantitative competitive RT-PCR analysis showed that eNOS production ( at 5 and 12 hours) and COX-2 production ( at 5 hours) were reduced at the gene expression level by asynchronous hemodynamics (SPA = - 180degrees) compared with synchronous hemodynamics (SPA = 0degrees), whereas ET-1 exhibited an opposite trend ( at 5 and 12 hours). NO, ET-1, and PGI(2) secretion followed their respective gene expression profiles after 5 and 12 hours. Conclusion - Together, these data suggest that highly asynchronous mechanical force patterns ( SPA = - 180degrees) can elicit proatherogenic vasoactive responses in endothelial cells at the gene expression level, indicating a novel mechanism that induces cardiovascular pathology.