Atherosclerosis is one of the leading causes of adult morbidity and mortality in the U.S. Atherosclerotic lesions develop as a result of diet and genetic disposition. In gene-targeted mice homozygous for an induced mutation in the apolipoprotein E gene (apoE-/-), atherosclerosis is induced by feeding a Western diet. An important component of atherosclerotic lesions is the presence of foam cells derived from blood monocytes which infiltrate the vessel wall at an early stage of lesion development. Candidate monocyte-endothelial adhesion molecules potentially involved in monocyte recruitment include the selectins, InterCellular Adhesion Molecule ICAM-I, beta2 (CD18) integrins, Vascular Cell Adhesion Molecule VCAM-1 and alpha4 integrins. This investigator proposes to investigate which leukocyte-endothelial adhesion molecules are involved in monocyte recruitment into atherosclerotic lesions in vivo. To this end, adhesion of monocytes and cell lines to arterioles and carotid arteries in vivo as well as to explanted carotid arteries mounted in a laminar flow chamber in vitro will be examined. The first specific aim is to identify the molecular interactions causing leukocyte rolling and adhesion in arterioles, intravital microscopy will be performed in the TNF-alpha treated mouse cremaster muscle preparation of wild type and mutant (knockout) mice lacking expression of P-selectin, E-selectin, CD 18, and ICAM- 1. In the second specific aim, molecules mediating leukocyte and monocyte adhesion and rolling in mouse carotid arteries will be determined. Direct adhesion of monocytes and cell lines transfected with monocyte adhesion molecules including P-selectin Glycoprotein Ligand PSGL-I will be monitored in vivo and in laminar flow chambers. In the third and final aim, the impact of the absence of P-selectin, E-selectin, CD18, and ICAM-1 on monocyte interactions with the luminal surface of atherosclerotic lesions will be assessed. The adhesion molecule-deficient mice will be bred to apoE-/- mice and monocyte and cell line adhesion to atherosclerotic carotid arteries will be investigated by intravital microscopy and flow chamber assays. Quantitative histology of carotid arteries will document the effect of the absence of each adhesion molecule on monocyte and foam cell content of lesions and the extent and time course of lesion development. The combination of gene-targeted mice with dynamic assessment of monocyte-vessel wall interactions constitutes a unique experimental approach to identify adhesion molecules critical for monocyte recruitment into atherosclerotic lesions in vivo. Studies such as this can provide a rational basis for the development of potential therapies targeting adhesion molecules.
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