Localized reduction of atherosclerosis in von Willebrand factor–deficient mice

Abstract

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. Introductionvon Willebrand factor (vWf) is a multimeric glycoprotein essential for thrombus formation at high shear stress. 1 It is found in plasma, platelet ␣-granules, Weibel-Palade bodies of endothelial cells, and the subendothelium. 2 Even though the involvement of vWf in thrombus formation at the site of atherosclerotic plaque rupture is well established, 3 the role of vWf in atherosclerotic lesion development is less clear. Several indications suggest that vWf may directly participate in plaque formation. First, Weibel-Palade bodies are found in great number at the sites of atherosclerotic lesions. 4 Second, oxidized low-density lipoprotein (LDL) and fluid mechanics, 2 factors involved in atherosclerotic lesion development, can induce Weibel-Palade body exocytosis. 5,6 Third, vWf expression is particularly prominent near branch points and bifurcations, areas prone to atherosclerotic lesion development. 7 Fourth, platelets may contribute to the atherosclerotic process by releasing growth factors after their vWf-dependent interaction with a damaged endothelial surface. 8,9 Experimental studies performed in pigs with von Willebrand disease (vWd), though supportive of a role for vWf in atherosclerosis, 3 have not been conclusive because of the genetic heterogeneity existing among the animals. 10 The recent generation of vWf-deficient mice has provided an opportunity to directly test the importance of vWf in atherosclerosis. Because mice are resistant to atherosclerosis, the vWf-deficient mice were first bred with an atherosclerosis...

Coexisting Pro-Inflammatory and Anti-Oxidative Endothelial Transcription Profiles in a Disturbed Flow Region of the Adult Porcine Aorta

“…Several adhesion-related molecules were differentially regulated by flow type, including von Willebrand factor, CD44, fibronectin 1, several integrins, cadherins, and junction plakoglobin. The up-regulation of von Willebrand factor (24) and CD44 (25) in particular may have implications for atherogenesis. However, VCAM-1, intercellular adhesion molecule 1, E-selectin, and P-selectin, all associated with early NF-B-mediated inflammatory responses and the onset of atherogenesis, were not detected as differentially expressed despite the increased transcriptional levels of proinflammatory cytokines and NF-B pathway components noted above.…”

“…Because this is the first in vivo study profiling regional endothelial gene expression on a large scale, we have attempted to bridge the findings to published candidate gene studies in vivo (21)(22)(23)(24) and experiments of flow disturbance in vitro (8,15,16,19,23). Furthermore, we have presented specific observations relating to some pathways that are central to atherogenesis.…”

“…This hypothesis has been addressed in principle by gene expression studies of cultured endothelium (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). However, it has only been addressed in vivo for a limited number of candidate genes and proteins (21)(22)(23)(24)(25).…”

“…Studies of candidate gene expression by endothelial cells (EC) in culture (12,18,23) and in knock-out animals (22,24,25) suggest that transcriptional activity is linked to flow disturbances. In EC cultures, unidirectional laminar shear stress (LSS) was correlated with protective profiles of gene expression (e.g., antioxidative, antiinflammatory, and͞or antiproliferative) when compared to the absence of flow (7-11, 13, 14, 17, 19) and selected examples of the protective genes have been shown to be expressed in endothelium in vivo (14,19).…”

Plaque, Platelets, and Plug – The Pathogenesis of Acute Coronary Syndrome

“…Both endothelial cell P-selectin and von Willebrand factor become the target for platelet GP1b (Theilmeier et al, 2002). A study using mice deficient of von Willebrand factor showed some level of protection from atherosclerosis thus elucidated the role of von Willebrand factor on plaque formation and progression in intact endothelial cells (Methia et al, 2001). …”