Tie1 Attenuation Reduces Atherosclerosis in a Dose Dependent and Shear Stress Specific Manner

Abstract

Although it is known that the response of endothelial cells to atherogenic disturbed flow is distinct from that elicited by non-atherogenic laminar flow, the mechanisms involved are poorly understood. Observing that expression of the endothelial receptor tyrosine kinase, Tie1, is evident only at regions of atherogenic flow in mature animals, we hypothesized that Tie1 plays a role in the endothelial response to atherogenic shear stress. Because deletion of Tie1 results in embryonic lethality secondary to vascular dysfunction, we utilized conditional and inducible mutagenesis (Tie1-/flox:SCL-ERT-Cre) to study the effect of Tie1 attenuation on atherogenesis in apolipoprotein E deficient (ApoE-/-) mice, and found a dose dependent decrease (70%) in atherosclerotic lesions. To test our hypothesis, we isolated primary aortic endothelial cells from Tie1flox/flox:SCL-ERT-Cre immorto mice and found 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 IkB-α expression while attenuating. In summary, we found that shear stress conditions that modulate atherogenic events also regulate Tie1 expression and Tie1 may play a novel pro-inflammatory role in atherosclerosis.