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^−/− P^+/+) and without P-selectin (apoE^−/− P^−/−) that were fed normal mouse chow. At 4 months of age, apoE^−/− P^−/− mice had 3.5-fold smaller aortic sinus lesions than apoE^−/− P^+/+ mice. These were limited to fatty streaks in the apoE^−/− P^−/− mice, whereas 70% of apoE^−/− P^+/+ lesions contained smooth muscle cells. Significantly more of the aortic sinus circumference was covered by lesions in the apoE^−/− P^+/+ animals. The P-selectin genotype affected macrophage recruitment, because twice as many mononuclear cells were present in the P-selectin–positive lesions. At 15 months, the lesions progressed to the fibrous plaque stage in both genotypes and spread throughout the aorta, but this process was delayed in apoE^−/− P^−/− mice. In the aortic sinus, the lesions of the apoE^−/− P^−/− mice were 2.6-fold smaller and less calcified.

Conclusions—P-selectin appears to be a key adhesion receptor mediating leukocyte recruitment into lesions and promoting advanced atherosclerosis in apoE-deficient mice.