P-and E-selectins are adhesion molecules mediating the first step in leukocyte extravasation. Because their function in leukocyte adhesion is overlapping, we hypothesized that there might be a combined effect of these selectins on the development of atherosclerotic lesions. We bred P-and E-selectin-double-deficient mice onto the low-density lipoprotein receptor (LDLR)-deficient background (LDLR Ϫ / Ϫ P/E Ϫ / Ϫ ) and compared lesion development in these mice to that in mice wild type for both selectins (LDLR Ϫ / Ϫ P/E ϩ / ϩ ). After 8 wk on atherogenic diet, the LDLR Ϫ / Ϫ P/E Ϫ / Ϫ mice developed fatty streaks in the aortic sinus that were five times smaller than those in LDLR Ϫ / Ϫ P/E ϩ / ϩ mice. The density of macrophages in the fatty streaks was comparable between LDLR Ϫ / Ϫ P/E ϩ / ϩ and LDLR Ϫ / Ϫ P/E Ϫ / Ϫ mice. After 22 wk on the diet, the lesions spread throughout the aorta but this process was delayed in LDLR Ϫ / Ϫ P/E Ϫ / Ϫ mice. At 37 wk on diet, the lesions progressed to the fibrous plaque stage in both genotypes. However, the lesions in the aortic sinus in LDLR Ϫ / Ϫ P/E Ϫ / Ϫ mice were 40% smaller and less calcified than those of LDLR Ϫ / Ϫ P/E ϩ / ϩ mice.
Background-Adhesive interactions between leukocytes and endothelial cells are characteristic of the development of atherosclerotic lesions, but the receptors involved remain to be defined. P-selectin is an adhesion receptor expressed on activated endothelial cells or platelets and was shown to be involved in fatty streak formation in LDL receptor-deficient mice on an atherogenic diet. The main purpose of this study is to examine the role of P-selectin in the spontaneous development of advanced atherosclerosis in apoE-deficient mice. Methods and Results-We intercrossed P-selectin-deficient mice with mice lacking apoE and compared lesion development in apoE-deficient mice with P-selectin (apoE Ϫ/Ϫ P ϩ/ϩ ) and without P-selectin (apoE Ϫ/Ϫ P Ϫ/Ϫ ) that were fed normal mouse chow. At 4 months of age, apoE Ϫ/Ϫ P Ϫ/Ϫ mice had 3.5-fold smaller aortic sinus lesions than apoE Ϫ/Ϫ P
P-selectin is expressed on activated endothelium and platelets where it can bind monocytes, neutrophils, stimulated T cells, and platelets. Because recruitment of these cells is critical for atherosclerotic lesion development, we examined whether P-selectin might play a role in atherosclerosis. We intercrossed P-selectin-deficient mice with mice lacking the low density lipoprotein receptor (LDLR) because these mice readily develop atherosclerotic lesions on diets rich in saturated fat and cholesterol. The atherogenic diet stimulated leukocyte rolling in the mesenteric venules of LDLR-deficient mice, and the increase in adhesiveness of the vessels was P-selectin-dependent. Most likely due to the reduced leukocyte interaction with the vessel wall, P-selectin-deficient mice on diet for 8-20 wk formed significantly smaller fatty streaks in the cusp region of the aortae than did P-selectin-positive mice. This difference was more prominent in males. At 37 wk on diet, the lesions in the LDLR-deficient animals progressed to the fibrous plaque stage and were distributed throughout the entire aorta; their size or distribution was no longer dependent on P-selectin. Our results show that P-selectin-mediated adhesion is an important factor in the development of early atherosclerotic lesions, and that adhesion molecules such as P-selectin are involved in the complex process of atherosclerosis.
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