Atherosclerosis is considered an inflammatory disease triggered by the entry of monocytes into the wall of large arteries, where they differentiate into macrophages and foam cells and promote growth and dedifferentiation of smooth muscle cells. Several adhesion molecules on endothelial cells, monocytes and platelets are relevant for the binding of monocytes. In order to investigate the molecular mechanisms of monocyte recruitment to atherosclerotic lesions, we have recently developed an ex vivo model in which monocytes or monocyte-like cell lines are perfused through carotid arteries isolated from apoE-/-mice, and their interaction with the vessel wall is investigated by intravital microscopy. Monocyte adhesion under flow depends on activation of integrins, which we hypothesize to be initiated by chemokines presented on the endothelial surface at lesion-prone sites. We recently found that platelets can also interact with the atherosclerotic endothelium in the carotid artery of apoE-/-, but not control mice. The overall hypothesis of this project is that specific chemokines expressed on atherosclerosis-prone endothelium trigger monocyte and platelet arrest through binding of integrins to their ligands. We propose to (1) measure the expression of adhesion molecules, chemokines, and chemokine receptors in apoE-/- mice by immunostaining and flow cytometry; (2) investigate the mechanisms by which monocytes roll, adhere and become activated at lesion-prone sites in arteries of apoE-/- mice by using our isolated-perfused carotid artery and response-to-injury models; (3) investigate the molecular mechanisms by which platelets roll and adhere at lesion-prone sites of the mouse carotid artery, and on established lesions; and (4) test the impact of inhibiting, eliminating or blocking adhesion molecules, chemokines and chemokine receptors identified in specified in specific aims 1, 2 and 3 on accelerated lesion development in apoE-/- mice undergoing controlled vascular injury by histology and MRI. We have already identified P-selectin, VCAM-1, PSGL-1 and VLA-4 as key adhesion molecules. We will now determine the roles of ICAM-1, CD18 integrins and selectin ligands. We focus on chemokines presented by the atherosclerotic endothelium that can arrest rolling monocytes or platelets, and their receptors on these cells. These studies are designed to (1) provide insight into the molecular mechanisms of monocyte and platelet recruitment to atherosclerotic lesions and (2) test their relevance in an established model of arterial injury in apoE-/- mice.
| Wolf, Dennis; Ley, Klaus (2015) Waking up the stem cell niche: how hematopoietic stem cells generate inflammatory monocytes after stroke. Circ Res 116:389-92 |
| Ge, Shuwang; Hertel, Barbara; Koltsova, Ekaterina K et al. (2013) Increased atherosclerotic lesion formation and vascular leukocyte accumulation in renal impairment are mediated by interleukin-17A. Circ Res 113:965-74 |
| Koltsova, Ekaterina K; Kim, Gisen; Lloyd, Kathleen M et al. (2012) Interleukin-27 receptor limits atherosclerosis in Ldlr-/- mice. Circ Res 111:1274-85 |
| Koltsova, Ekaterina K; Garcia, Zacarias; Chodaczek, Grzegorz et al. (2012) Dynamic T cell-APC interactions sustain chronic inflammation in atherosclerosis. J Clin Invest 122:3114-26 |
| Galkina, Elena V; Butcher, Matthew; Keller, Susanna R et al. (2012) Accelerated atherosclerosis in Apoe-/- mice heterozygous for the insulin receptor and the insulin receptor substrate-1. Arterioscler Thromb Vasc Biol 32:247-56 |
| Wingender, Gerhard; Hiss, Marcus; Engel, Isaac et al. (2012) Neutrophilic granulocytes modulate invariant NKT cell function in mice and humans. J Immunol 188:3000-8 |
| Doran, Amanda C; Lipinski, Michael J; Oldham, Stephanie N et al. (2012) B-cell aortic homing and atheroprotection depend on Id3. Circ Res 110:e1-12 |
| Koltsova, Ekaterina K; Ley, Klaus (2011) How dendritic cells shape atherosclerosis. Trends Immunol 32:540-7 |
| von Vietinghoff, Sibylle; Koltsova, Ekaterina K; Mestas, Javier et al. (2011) Mycophenolate mofetil decreases atherosclerotic lesion size by depression of aortic T-lymphocyte and interleukin-17-mediated macrophage accumulation. J Am Coll Cardiol 57:2194-204 |
| Ley, Klaus; Miller, Yury I; Hedrick, Catherine C (2011) Monocyte and macrophage dynamics during atherogenesis. Arterioscler Thromb Vasc Biol 31:1506-16 |
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