IDENTIFICATION OF VASCULAR ENDOTHELIAL GENES DIFFERENTIALLY RESPONSIVE TO FLUID MECHANICAL STIMULI - CYCLOOXYGENASE-2, MANGANESE SUPEROXIDE-DISMUTASE, AND ENDOTHELIAL-CELL NITRIC-OXIDE SYNTHASE ARE SELECTIVELYUP-REGULATED BY STEADY LAMINAR SHEAR-STRESS

Early atherosclerotic lesions develop in a topographical pattern that strongly suggests involvement of hemodynamic forces in their pathogene sis. We hypothesized that certain endothelial genes, which exhibit dif ferential responsiveness to distinct fluid mechanical stimuli, may par ticipate in the atherogenic process by modulating, on a local level wi thin the arterial wall, the effects of systemic risk factors, A differ ential display strategy using cultured human endothelial cells has ide ntified two genes, manganese superoxide dismutase and cyclooxygenase-2 , that exhibit selective and sustained up-regulation by steady laminar shear stress (LSS). Turbulent shear stress, a nonlaminar fluid mechan ical stimulus, does not induce these genes, The endothelial form of ni tric oxide synthase also demonstrates a similar LSS-selective pattern of induction. Thus, three genes with potential atheroprotective (antio xidant, antithrombotic, and antiadhesive) activities manifest a differ ential response to distinct fluid mechanical stimuli, providing a poss ible mechanistic link between endothelial gene expression and early ev ents in atherogenesis. The activities of these and other LSS-responsiv e genes may have important implications for the pathogenesis and preve ntion of atherosclerosis.