von Willebrand Factor Does Not Influence Atherogenesis in Arteries Subjected to Altered Shear Stress

Nichols, Timothy C.; Bellinger, Dwight A.; Reddick, Robert L.; Koch, Gary G.; Sigman, Jeff; Erickson, Geoffrey R.; Laney, Tracey du; Johnson, Timothy A.; Read, Marjorie S.; Griggs, Thomas R.

doi:10.1161/01.atv.18.2.323

Cited by 13 publications

(12 citation statements)

References 57 publications

(43 reference statements)

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“…On the other hand, a study of von Willebrand disease in pigs has indicated that vWF was not essential for neointimal development in normal carotid and femoral arteries. 45 In this study, a bolus injection of monoclonal antibody against vWF reduced not only thrombus formation but also subsequent neointimal SMC proliferation and neointimal development after the second balloon injury. Our result supports an important role for vWF in neointimal growth.…”

Section: Discussionmentioning

confidence: 56%

Contribution of von Willebrand Factor to Thrombus Formation on Neointima of Rabbit Stenotic Iliac Artery Under High Blood-Flow Velocity

Yamashita

Asada²,

Sugimura³

et al. 2003

ATVB

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Objective-It has become clear that von Willebrand factor (vWF) plays important roles in platelet adhesion and aggregation under high blood-flow velocity conditions observed in stenotic atherosclerotic arteries. However, its roles in thrombus formation in vivo on diseased arteries have not been fully understood. We examined the contribution of vWF to thrombus formation and subsequent intimal growth by using a repeated balloon-injury model in rabbits. Methods and Results-Rabbit iliac arteries 4 weeks after a first balloon injury showed 37% luminal stenosis by neointimal growth, and blood velocity increased by 2.1 times compared with that of uninjured arteries. The second balloon injury induced fibrin-rich thrombus formation on the injured neointima. Intravenous administration of a monoclonal antibody against vWF (AJW200, 1.0 mg/kg body weight) remarkably prevented botrocetin-induced platelet aggregation ex vivo for 2 days; moreover, thrombus formation, cell proliferation, and subsequent neointimal growth were significantly reduced at 30 minutes, 5 days, and 4 weeks, respectively, after the second balloon injury. Conclusions-These results indicate that vWF plays a potent role in fibrin-rich thrombus formation on the neointima under high blood-flow velocity conditions. Inhibition of plasma vWF activity might be effective for the reduction of thrombus formation and/or subsequent neointimal development after coronary interventions. T hrombus formation on a disrupted atherosclerotic plaque is a threatening event that leads to acute coronary syndromes. 1,2 Because platelet adhesion and aggregation are essential steps in hemostatic and thrombotic processes, the development of platelet-rich thrombi has been regarded as a trigger of acute coronary syndromes. 2,3 On the other hand, autopsy studies have revealed that thrombi that have caused myocardial infarction contain not only platelets but also a large amount of fibrin, suggesting increased activation of the coagulation cascade at the time of the event. 4,5 We and other investigators have demonstrated that tissue factor (TF) is expressed in atherosclerotic lesions, 6 -9 is an important determinant of thrombogenicity, and contributes to fibrin-rich thrombus formation after plaque disruption. 7,10 Recent angiographic studies have revealed that coronary occlusions that induce myocardial infarction most frequently evolve in segments with stenoses that are Ͻ80%. 11 On the basis of this evidence, fluid-dynamic forces (elevated shear rates) would be expected to have certain effects on thrombus formation in the stenotic arteries. Current ex vivo experiments have indicated a crucial role for von Willebrand factor (vWF) in platelet aggregation under rapid-flow conditions. 12,13 In addition, inhibition of vWF activity prevents in vivo arterial platelet thrombus formation in the normal arteries of some species. 14 -16 However, the actual role of vWF in thrombus formation in stenotic, atherosclerotic arteries has not been elucidated.We therefore examined whether or not vWF contribute...

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Section: Discussionmentioning

confidence: 56%

Contribution of von Willebrand Factor to Thrombus Formation on Neointima of Rabbit Stenotic Iliac Artery Under High Blood-Flow Velocity

Yamashita

Asada²,

Sugimura³

et al. 2003

ATVB

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“…Furthermore, homozygote vWF deficient pigs show a resistance to the initiation and progression of spontaneous and diet-induced atherosclerosis, 41 but vWF appeared not essential for shear-induced smooth muscle cell accumulation in the intima. 7 Therefore, the vWF deposits seem not to be important for this early step in the development of atherosclerosis. However, deposition of vWF could play a role in a later step of atherogenesis.…”

Section: De Meyer Et Al Intimal Deposition Of Von Willebrand Factormentioning

confidence: 97%

“…6 Accumulation of vWF in intimal thickening may be the result of increased synthesis and release by ECs, an influx from the plasma and/or platelets, or a decreased rate of removal of vWF from the extracellular matrix. 7 The aim of the present study was to investigate whether the intimal deposition of vWF is due to an increased synthesis of the protein and whether subendothelial deposition of vWF also occurs after cholesterol-induced plaque formation and whether this has functional consequences for platelet adhesion.…”

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confidence: 99%

Intimal Deposition of Functional von Willebrand Factor in Atherogenesis

Meyer

Hoylaerts

Kockx

et al. 1999

ATVB

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Abstract-During the formation of intimal thickening in normocholesterolemic rabbits, von Willebrand factor (vWF) is increased in the endothelial cells (ECs) and deposited in the intima. We investigated whether this also occurs during cholesterol-induced plaque formation, whether the synthesis of vWF increases, and whether this influences platelet adhesion. Rabbits were fed a cholesterol-rich (0.3%) diet for 26 weeks. Thereafter, half of the animals received a normal diet for another 26 weeks (cholesterol withdrawal). To induce intimal thickening in normocholesterolemic rabbits, collars were positioned around the carotid artery. Arterial segments were studied using immunohistochemistry, reverse transcription-polymerase chain reaction, electron microscopy, and platelet adhesion tests. Cholesterol treatment induced plaque formation in the aorta. The ECs had a cuboidal aspect, showed a dense immunoreactivity for vWF, a pronounced rough endoplasmic reticulum, and numerous Weibel-Palade bodies. There were subendothelial vWF deposits in the plaques and vWF mRNA was significantly increased as compared with controls. Similar changes were seen after collar-induced intimal thickening. After cholesterol withdrawal, both vWF mRNA and the ultrastructural morphology of the ECs normalized, and the vWF deposits disappeared from the plaque. Perfusion studies with anticoagulated rabbit blood over cross-sections of atherosclerotic aortas revealed increased vWF-mediated platelet adhesion in the subendothelial plaque region. Whereas rabbit platelets perfused through the lumen adhered to the same extent to de-endothelialized aortas of normocholesterolemic and atherosclerotic rabbits, vWF mediated platelet adhesion to endothelium was observed in atherosclerotic but not in normal aortas. Our results show an increased synthesis and (sub)endothelial presence of vWF after vascular injury, with functional consequences for platelet deposition on the vessel wall.

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“…Finally, vWf plays an important role not only in platelet adhesion and aggregation but also in coagulation 42,43 and may thus enhance the risk of thrombogenesis. Accordingly, the increase of vWf within 48 hours after a myocardial infarction was a predictor of the rate of restenotic cardiovascular events within 14 days, whereas the increase of CRP, as a marker of acute-phase response, was not.…”

Section: Jager Et Al Vwf and Crp As Predictors Of Mortality 3075mentioning

confidence: 99%

von Willebrand Factor, C-Reactive Protein, and 5-Year Mortality in Diabetic and Nondiabetic Subjects

Jager

Hinsbergh

Kostense

et al. 1999

ATVB

286

190

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Abstract-Increased levels of von Willebrand factor (vWf) and C-reactive protein (CRP) predict cardiovascular mortality in selected populations. It is uncertain whether vWf and CRP predict mortality in a general population and whether vWf and CRP predict mortality through similar pathways. This study investigated the association of vWf and CRP with cardiovascular and all-cause mortality among diabetic and nondiabetic subjects. An age-, sex-, and glucose tolerance-stratified sample (nϭ631) of a population-based cohort aged 50 to 75 years was followed prospectively for 5 years. After 5 years of follow-up, 58 subjects had died (24 of cardiovascular causes). vWf (Ͼ1.56 IU/mL) and CRP (Ͼ2.84 mg/L) levels in the upper tertile were associated with, respectively, a 3-and 2-fold increase in cardiovascular mortality after adjustment for age, sex, and glucose tolerance status. Analyses in nondiabetic and diabetic subjects separately gave similar results. After further adjustment for hypertension, levels of HDL cholesterol and triglyceride, smoking habits, ischemic heart disease, and peripheral arterial disease, the relative risks (RRs) were 3.0 (95% CI 1.2 to 7.9) for vWf and 1.4 (95% CI 0.6 to 3.5) for CRP. When both vWf and CRP were included in the latter multivariate analysis, the RRs were 3.0 (95% CI 1.1 to 7.9) for vWf and 1.3 (95% CI 0.5 to 3.4) for CRP. The association between vWf and risk of cardiovascular mortality was independent of blood group (O versus non-O) and, moreover, similar among subjects with different blood groups. Repeating the analyses for all-cause mortality gave similar results for CRP. For vWf, the RR was 2.0 (95% CI 1.1 to 3.5) after adjustment for all other risk factors. Increased levels of vWf are independently associated with cardiovascular and all-cause mortality in both diabetic and nondiabetic subjects. The association between increased levels of CRP and cardiovascular mortality was partly explained by other risk factors.

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von Willebrand Factor Does Not Influence Atherogenesis in Arteries Subjected to Altered Shear Stress

Cited by 13 publications

References 57 publications

Contribution of von Willebrand Factor to Thrombus Formation on Neointima of Rabbit Stenotic Iliac Artery Under High Blood-Flow Velocity

Contribution of von Willebrand Factor to Thrombus Formation on Neointima of Rabbit Stenotic Iliac Artery Under High Blood-Flow Velocity

Intimal Deposition of Functional von Willebrand Factor in Atherogenesis

von Willebrand Factor, C-Reactive Protein, and 5-Year Mortality in Diabetic and Nondiabetic Subjects

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