Prominent role of P-selectin in the development of advanced atherosclerosis in apoE-deficient mice

Background-Adhesive interactions between leukocytes and endothelial cells are characteristic or 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 rule 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.