Objective Arteries and veins are molecularly distinct. However, whether the intrinsic differences contribute to the different atherosclerosis susceptibility between arteries and veins has remained unknown. This study was to investigate whether COUP-TFII, a key molecular in regulating embryonic arterial-venous differentiation, is implicated in the regulation of processes controlling atherosclerosis. Methods The endothelium of the vein but not the artery of adult vessels in vivo expressed COUP-TFII transcription factor, and the endothelial cells (EC) from human umbilical veins in in vitro culturing began to express some level of arterial EC markers including Jaggedl and Notchl after COUP-TFII was knock down, indicating the key role of COUP-TFII in maintaining of proper arterial-venous demarcation in the adult. Results Gene profiles showed that the venous EC with or without Ang II exposure (1×10-7 mol/L, 4 h) both displayed different gene expression pattern with more atherogenic genes upregulated after COUP-TFII was knock down (P<0.05 and fold change≥2). These genes represented various atherosclerosis-related pathways including lipid transfer and metabolism, adhesion molecular, thrombosis formation, and inflammation pathways. Moreover, the in vitro cell functional assay showed that COUP-TFII knock down in venous EC not only increased the basal but also Ang II induced THP1-EC cell adhesion. Conclusion COUP-TFII influences the gene transcription of atherosclerosis and adhesion function of EC through multiple mechanisms, suggesting, at least at the cellular and gene expression level, that the intrinsic molecular differences between arteries and veins might contribute to their different atherosclerotic susceptibility besides local environment. Objectiveseries and veins are molecularly distinct. However, whether the intrinsic differences contribute to the different atherosclerosis susceptibility between arteries and veins has remained unknown. This study was to investigate whether COUP-TFII, a key molecular in regulating embryonic arterial-venous differentiation, is Methods The endothelium of the vein but not the artery of adult vessels in vivo expressed COUP-TFII transcription factor, and the endothelial cells (EC) from human umbilical veins in in vitro culturing began to express some level of arterial EC markers including Jaggedl and Notchl after COUP-TFII was knock down, indicating the key role of COUP-TFII in maintaining of proper arterial-venous demarcation in the adult. Results Gene profiles showed that the venous EC with or without Ang II exposure (1 × 10-7 mol / L, 4 h) both displayed different gene expression pattern with more atherogenic genes up regulated after COUP-TFII was knocked down (P <0.05 and fold change> 2). These genes represented various atherosclerosis-related pathways including lipid transfer and metabolism, adhesion molecular, thrombosis formation, and inflammation pathways. assay showed that COUP-TFII knockdown in venous EC not only increased the basal but also Ang II induced THP1-EC cell adhesion. Conclusion COUP-TFII influences the gene transcription of atherosclerosis and adhesion function of EC through multiple mechanisms, suggesting, at least at the cellular and gene expression level, that the intrinsic molecular differences between arteries and veins might contribute to their different atherosclerotic susceptibility besides local environment.