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 lacking the low-density lipoprotein receptor (LDLR-/-) on a C57BL/6J background. LDLR-/-vWf+/+ and LDLR-/-vWf-/- mice were placed on a diet rich in saturated fat and cholesterol for different lengths of time. The atherogenic diet 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 aortic sinus of LDLR-/-vWf-/- mice of either sex were 40% smaller and contained fewer monocytes than those in LDLR-/-vWf+/+ mice. After 22 weeks on the atherogenic diet (early fibrous plaque stage), the difference in lesion size 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 branch 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 disturbed flow that are prone to atherosclerosis. Thus, vWf may recruit platelets/leukocytes to the lesion in a flow-dependent manner or may be part of the mechano-transduction pathway regulating endothelial response to shear stress.
Methia
N
N
Center for Blood Research and the Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
André
P
P
Denis
C V
CV
Economopoulos
M
M
Wagner
D D
DD
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001011:Aorta / Q000473:pathology; D001018:Aortic Diseases / Q000150:complications / Q000235:genetics / Q000473:pathology; D001161:Arteriosclerosis / Q000097:blood* / Q000150:complications / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte; D003433:Crosses, Genetic; D004036:Diet, Atherogenic; D005260:Female; D020022:Genetic Predisposition to Disease; D039661:Integrin beta3; D007962:Leukocytes / Q000473:pathology; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012850:Sinus of Valsalva / Q000473:pathology; D014842:von Willebrand Diseases / Q000150:complications* / Q000235:genetics / Q000473:pathology; D014841:von Willebrand Factor / Q000235:genetics / Q000502:physiology*
D015703:Antigens, CD; D039661:Integrin beta3; D008024:Ligands; D010980:Platelet Membrane Glycoproteins; D011973:Receptors, LDL; D014841:von Willebrand Factor