Although the response of endothelial cells to the disturbed blood flow in the vicinity of atherosclerotic lesions is known to be distinct from that elicited by nonatherogenic laminar flow, the mechanisms involved are poorly understood. Our initial studies confirmed that expression of the endothelial receptor tyrosine kinase Tie1 was evident at regions of atherogenic flow in mature animals. We therefore hypothesized that Tie1 plays a role in the endothelial response to atherogenic shear stress. Consistent with this, we found that Tie1+/- mice bred to the apoE-deficient background displayed a 35% reduction in atherosclerosis relative to Tie1+/+;Apoe-/- mice. Since deletion of Tie1 results in embryonic lethality secondary to vascular dysfunction, we used conditional and inducible mutagenesis to study the effect of endothelial-specific Tie1 attenuation on atherogenesis in Apoe-/- mice and found a dose-dependent decrease in atherosclerotic lesions. Analysis of primary aortic endothelial cells indicated that atheroprotective laminar flow decreased Tie1 expression in vitro. Attenuation of Tie1 was associated with an increase in eNOS expression and Tie2 phosphorylation. In addition, Tie1 attenuation increased IkBα expression while decreasing ICAM levels. In summary, we have found that shear stress conditions that modulate atherogenic events also regulate Tie1 expression. Therefore, Tie1 may play a novel proinflammatory role in atherosclerosis.