Spontaneous and diet-induced coronary atherosclerosis in normal swine and swine with von Willebrand disease.

Fuster, Valentı́n; Lie, J T; Badimón, Lina; Rosemark, J A; Badimon, Juan J.; Bowie, E. J. W.

doi:10.1161/01.atv.5.1.67

Cited by 55 publications

(29 citation statements)

References 17 publications

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“…6,24 These findings are supported by the results of a recently published study in mice with a complete deficiency of vWF. 9 Because vWF plays a role in primary and secondary hemostasis, protection against atherosclerosis could be explained by decreased adhesion and aggregation of platelets to endothelial and subendothelial structures [25][26][27] and by decreased plasmatic coagulability.…”

Section: Discussionsupporting

confidence: 69%

“…In the pigs, protection against aortic atherosclerosis was found, whereas no protection was found in the coronary arteries. 8,24,31,32 It is known that the pace of development of atherosclerosis is different for the various sites in the vessel tree, depending on some recognized factors, such as shear stress, and some as yet unknown factors. 33 In the present study, we found advanced atherosclerotic lesions and found no differences between groups.…”

Section: Discussionmentioning

confidence: 99%

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Patients With Type 3 Severe von Willebrand Disease Are Not Protected Against Atherosclerosis

et al. 2004

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Background-The results of a number of studies in pigs and mice suggest that absence of von Willebrand factor (vWF) protects against the development of atherosclerosis. We studied whether patients with a complete deficiency of vWF (type 3 von Willebrand disease [vWD]) develop fewer atherosclerotic vessel wall changes than healthy controls. Methods and Results-This study included 47 individuals with type 3 vWD and 84 healthy controls. Early atherosclerotic changes were assessed by measuring the thickness of the intima-media in the carotid and femoral arteries by B-mode ultrasonography. Advanced atherosclerotic changes were quantified by summing the maximal thickness of atherosclerotic plaques in the carotid and femoral arteries and were expressed as a plaque score. Established risk factors were determined to adjust for possible differences between the groups. We found no substantial difference in intima-media thickness between vWD patients and controls (adjusted difference for carotid artery 0.007 mm, 95% CI Ϫ0.022 to 0.036 mm; femoral artery 0.069 mm, 95% CI Ϫ0.056 to 0.19 mm). Similar proportions of patients and controls had atherosclerotic plaques (19% and 17%, respectively). No difference was found in the plaque score between groups (adjusted difference Ϫ0.22 mm, 95% CI Ϫ0.69 to 0.26). Among vWD patients, we found no effect of treatment with vWF concentrates on intima-media thickness or plaque score. Conclusions-The results of this study indicate that vWF does not play a substantial role in human atherogenesis.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Patients With Type 3 Severe von Willebrand Disease Are Not Protected Against Atherosclerosis

et al. 2004

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“…The first experimental data suggested that the absence of vWf provided an atheroprotective effect in pigs. 23,24 However, it was later shown that the atherogenic diet leads to a variable degree of hypercholesterolemia caused by a polymorphism in apolipoprotein B100, 10,25 making it difficult to draw a definitive conclusion about the involvement of vWf in atherosclerosis. In contrast, mice deficient in vWf represented a model with a defined genetic background and allowed us to show in the present study that the absence of vWf significantly delays the formation of atherosclerotic lesions in mice on the LDLR-deficient background.…”

Section: Discussionmentioning

confidence: 99%

Localized reduction of atherosclerosis in von Willebrand factor–deficient mice

Methia

André

Denis

et al. 2001

Blood

189

153

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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...

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“…6 7 8 Also intriguing is the possible relationship between our finding of no detectable vWF in normal swine coronary arteries and the finding of a low frequency of spontaneous coronary atherosclerosis in normal, as well as von Willebrand disease, pigs. 22 Further studies will be necessary to explore the potential relationship between vWF in this site and its proclivity toward atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Distribution of von Willebrand factor in porcine intima varies with blood vessel type and location.

Rand¹,

Badimón²,

Gordon³

et al. 1987

Arteriosclerosis

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The von Willebrand factor (vWF) has been generally accepted as a marker for endothellal cells. In a systematic Immunolocallzatlon study of porcine blood vessels that used Indirect Immunofluorescence with a monospeclflc polyclonal anti-vWF and two monoclonal anti-vWFs, we observed that vWF Is not universally distributed in Intact, fresh endothella. vWF Is consistently localized In veins, with the exception of the pulmonlc vein. In arteries, vWF Is generally absent except for areas of the distal abdominal aorta, the vaso vasorum of the thoracic aorta, and the pulmonlc artery. We conclude that there are regional differences In the distribution of vWF In the various endothellal beds of pigs. (Arteriosclerosis 7:287-291, May/June 1987) T he von Willebrand factor (vWF) is a high molecular weight muttimeric glycoproteln that promotes platelet adhesion to exposed vascular subendothelium and subsequent platelet thrombus formation.12 Immunolocalization of vWF has been an accepted criterion for identifying endothelial cells and has been applied for that purpose for the validation of tissue culture systems and for histopathologic diagnosis. There is evidence that vWF may play a role in atherogenesis. Pigs with von Willebrand disease have been found to be resistant to aortic arteriosclerosis.8 -7i 8> 9 Since it is possible that this resistance may be due to impairment of the platelet interaction with the arterial wall, we planned to investigate whether vWF is uniformly distributed in swine intima in vivo.In addition, any possible differences in vWF distribution in different blood vessels could be an important factor to consider in further investigations of the platelet-vessel wall interaction in pigs. Using immunolocalization techniques, we found that the distribution of vWF in pigs is not homogeneous throughout the vasculature and differs markedly from that observed in the human vasculature. Methods TissuesThe procedures performed in this study were all in accordance with appropriate institutional guidelines and also followed the American Heart Association guidelines for animal research. Three normal pigs and two pigs homozygous for von Willebrand disease (vWF:Ag < 3% in plasma) were used for these studies. Porcine blood was collected into 0.11 M sodium citrate and was spun at 250 gfor This work was supported by Grants HL-32200 and HL-17430 from the National Heart, Lung and Blood Institute, National Institutes of Health.Address . Blood vessels and tissues were collected immediately after sacrifice. The blood vessels were handled as carefully as possible to avoid mechanical or air deendothelialization. Bone marrow was collected by aspiration, then smears were made onto glass slides. Because of the surprising results of pilot studies, which showed no detectable immunofluorescence for vWF in arteries, the tissues (other than bone marrow and platelets) were treated in three different ways before application onto glass slides for immunofluorescence. The treatment included: 1) immediate fixation in 2% paraformaldehyde dissolved I...

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Spontaneous and diet-induced coronary atherosclerosis in normal swine and swine with von Willebrand disease.

Cited by 55 publications

References 17 publications

Patients With Type 3 Severe von Willebrand Disease Are Not Protected Against Atherosclerosis

Patients With Type 3 Severe von Willebrand Disease Are Not Protected Against Atherosclerosis

Localized reduction of atherosclerosis in von Willebrand factor–deficient mice

Distribution of von Willebrand factor in porcine intima varies with blood vessel type and location.

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