Laminar shear stress (LSS) caused by blood flow is known to regulate endothelial function and to contribute to vascular health. By way of contrast, endothelial cell senescence seems to increase the incidence of vascular disorders. In an attempt to identify genes associated with vascular health/disease states, this study assessed the differential gene expression of young and senescent human umbilical vein endothelial cells (HUVECs) under static and LSS conditions. Replicative cell senescence was induced by continuous subculture in vitro, and LSS was provided using a cone-and-plate device. Young (p4) and senescent (p18) cells were subjected to LSS at 12 dyn.cm(-2) or maintained under static conditions for 24 h. Total mRNA was subjected to cDNA microarray analysis using the Affymetrix GeneChip. Welch t test at a significance level of p < 0.05 provided 961 "LSS-responsive" genes, whose expression was altered by LSS in both young and senescent cells, and 529 "senescence-responsive" genes differentially expressed in young vs senescent cells under both static and LSS conditions. The LSS-responsive and senescence-responsive gene groups included 74 genes held in common; these may prove useful for the study of cellular responses commonly affected by LSS and senescence. Among them, 20 genes whose expression was increased by LSS and simultaneously decreased by cellular senescence are suggested as potential vascular health markers in the sense that LSS is antiatherogenic, whereas senescence is proatherogenic. These genes included argininosuccinate synthetase 1, which was determined to be critical for both basal and LSS-induced NO production in young HUVECs. Furthermore, its diminished expression, and not that of nitric oxide synthase 3, was implicated in the insufficient NO production exhibited by senescent HUVECs under LSS conditions. The genes identified in this study are expected to facilitate improvements in our current level of understanding regarding endothelial physiology in association with age-associated vascular disease.