Absence of P-selectin delays fatty streak formation in mice.

Abstract

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.

Prominent Role of P-Selectin in the Development of Advanced Atherosclerosis in ApoE-Deficient Mice

“…As described in the introduction, using LDLR-deficient mice fed the atherogenic diet, we found that the absence of P-selectin partially reduces fatty streak formation but does not affect the more advanced stages of atherosclerosis. 8 The present study is the first to demonstrate that P-selectin is also important for lesion growth at the fibrous plaque stage.…”

“…The sections containing aortic sinus were prepared as described, 8 with modifications. The heart and attached aorta were fixed in 4% paraformaldehyde for 30 minutes before being embedded in OCT compound.…”

“…At 37 weeks on the diet, the lesions in the LDLR Ϫ/Ϫ animals progressed to the fibrous plaque stage, and lesion size and distribution were no longer dependent on P-selectin. 8 The atherogenic "Paigen" diet 9,10 includes an artificially high cholesterol content (10 to 20 times that of a Western-type diet) plus the unnatural dietary constituent cholic acid. This diet could produce unintended pathophysiological processes in these animals.…”

ICAM-1 Deficiency Reduces Atherosclerotic Lesions in Double-Knockout Mice (ApoE − /− /ICAM-1 − /− ) Fed a Fat or a Chow Diet

“…24 It should be noted that ICAM-1 expression is only part of the mechanism implicated in the homing of leukocytes to sites of vascular lesions; other adhesion molecules, for instance, P-selectin, have been implicated in gene-deleted mice. 43 Furthermore, knocking out MCP-1 or its receptor in LDL Ϫ/Ϫ or ApoE Ϫ/Ϫ mice, respectively, will also significantly decrease lesion formation. 44,45 In conclusion, adhesion and transmigration mediated by several interacting molecular mechanisms appear to be essential for monocyte traffic in atherosclerosis, and this study provides further evidence of the importance of these phenomena in the pathogenesis of the disease.…”

VCAM-1 is critical in atherosclerosis

“…In the more realistic apoE knockout model of atherosclerosis, in which mice have cholesterol levels between 500 and 2,000 mg/dl, depending on the diet offered, animals lacking P-selectin or ICAM-1 show significantly smaller aortic lesions (13,14). In a milder model of atherosclerosis, the LDL receptor knockout mouse, absence of P-selectin showed only a modest benefit in male mice and no benefit in female mice (15).…”