Localized reduction of atherosclerosis in von Willebrand factor-deficient mice

To examine the role of the platelet adhesion molecule von Willebrand factor (vWf) In atherogenesis, vWf-deficient mice (vWf-/-) were bred with mice la cking the low-density lipoprotein receptor (LDLR-/-) on a C57BL/6J backgrou nd. LDLR-/-vWf+/+ and LDLR-/-vWf-/- mice were placed on a diet rich In satu rated fat and cholesterol for different lengths of time. The atherogenic di et stimulated leukocyte rolling in the mesenteric venules in both genotypes , Indicating an Increase in P-selectin-mediated adhesion to the endothelium . After 8 weeks on the atherogenic diet, the fatty streaks formed in the ao rtic sinus of LDLR -/-vWf-/- mice of either sex were 40% smaller and contai ned fewer monocytes than those In LDLR-/-vWf+/+ mice. After 22 weeks on the atherogenic diet (early fibrous plaque stage), the difference In lesion si ze in the aortic sinus persisted. Interestingly, the lesion distribution in the aortas of LDLR-/-vWf-/- animals was different from that of LDLR-/-vWf/+ animals. In vWf-positive mice, half of all lesions were located at the b ranch points of the renal and mesenteric arteries, whereas lesions in this area were not as prominent In the vWf-negative mice. These results indicate that the absence of vWf primarily affects the regions of the aorta with di sturbed flow that are prone to atherosclerosis. Thus, vWf may recruit plate lets/leukocytes to the lesion in a flow-dependent manner or may be part of the mechano-transduction pathway regulating endothelial response to shear s tress. (C) 2001 by The American Society of Hematology.