Role of Tie-1 in Vascular Inflammation and Atherosclerosis

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DESCRIPTION (provided by applicant): The long-term goal of this study is to examine the role of Tie-1 in vascular inflammation and atherosclerosis. Tie-1 is upregulated at atherosclerosis-prone arterial branch points and in atherosclerotic lesions. We postulate that Tie-1 activation at these sites is one of the precipitating molecular events that initiates the development of atherosclerosis. Indeed, we have evidence to show that Tie-1 activity in vitro induces endothelial inflammation. The experiments proposed in this grant are designed to probe the connection between Tie-1 and atherosclerosis and to gain mechanistic understanding of the disease at the molecular level. Specifically, we propose: 1) To study the proinflammatory property of Tie-1 in endothelial cells in vitro by examining the roles of ICAM-1, VCAM-1, E-selectin, IL-6, and IP-10 using both mono-cell-type culture experiments and an artificial arterial wall reconstruction model; 2) To dissect signaling pathways responsible for Tie-1-induced inflammatory response by elucidating the mechanism of activation of p38 MAP kinase and by identifying tyrosine-phosphorylated proteins via functional proteomics and ; 3) To study the role of Tie-1 in inflammation and atherosclerosis development in vivo by using a collagen-fibronectin gel implantation mouse model and a transgenic mouse line that conditionally expresses Tie-1 in an endothelial specific manner. Results from these experiments may shed light on the question why atherosclerotic lesions tend to develop at particular vascular sites. This proposal is highly relevant to the mission of NIDDK, because atherosclerosis affects kidney function. Atherosclerosis is the main cause of renal artery stenosis (RAS), accounting for 90% of the cases. RAS causes narrowing of the renal artery and reduction in renal perfusion, resulting in hypertension. Ultimately, ischemic nephropathy can occur, leading to end stage renal failure. Atherosclerotic plaques in RAS usually develop at the ostium of the renal artery. Strikingly, Tie-1 is dramatically upregulated at the aorta-renal artery junction. Therefore, understanding the role of Tie-1 in atherosclerosis may have a direct impact on the prevention of RAS. Atherosclerosis is one of the major health problems in western countries. An improved mechanistic understanding of vascular inflammation leading to atherosclerosis will yield invaluable information necessary for diagnostic and/or therapeutic purposes.