von Willebrand factor and occlusive arterial thrombosis. A study in normal and von Willebrand's disease pigs with diet-induced hypercholesterolemia and atherosclerosis.

Nichols, Timothy C.; Bellinger, Dwight A.; Tate, David A.; Reddick, Robert L.; Read, Marjorie S.; Koch, Gary G.; Brinkhous, K. M.; Griggs, Thomas R.

doi:10.1161/01.atv.10.3.449

Cited by 59 publications

(39 citation statements)

References 34 publications

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“…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%

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: Discussionmentioning

confidence: 99%

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

et al. 2004

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“…Second, it has been reported that pigs with von Willebrand disease, similar to human type 3 von Willebrand disease (ie, no vWF antigen), are relatively protected against diet-induced atherosclerosis. 34,35 This finding has been attributed to the lack of vWF-mediated platelet adhesion to the subendothelium as an important contributing event to atherogenesis. In view of the findings on the sequestering and subsequent storage of P-selectin by multimeric vWF, we suggest that the protection from atherosclerosis in vWF-deficient pigs may be accounted for by the absence of vWF and the subsequent deficient availability of P-selectin.…”

Section: Discussionmentioning

confidence: 99%

Assembly of Multimeric von Willebrand Factor Directs Sorting of P-Selectin

Hop

Guilliatt

Daly

et al. 2000

ATVB

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Abstract-We designed a model system to study the role of von Willebrand factor (vWF) in the sorting of P-selectin and the biogenesis of Weibel-Palade body (WPB)-like organelles. For that purpose, a human epithelial cell line (T24) that synthesizes P-selectin mRNA, but which is devoid of vWF mRNA synthesis and storage organelles, was transfected with full-length vWF cDNA or a deletion mutant thereof. Stable transfectants of T24 with full-length vWF cDNA revealed the generation of WPB-like organelles as demonstrated by colocalization of vWF and P-selectin with double-labeling immunofluorescence. In contrast, T24 cells transfected with vWF delD'D3 cDNA, encoding a mutant that is unable to form vWF multimers, displayed only perinuclear vWF staining, whereas no indication was found for the presence of WPB-like organelles. The contents of the organelles in full-length vWF cDNA-transfected T24 cells were released on activation of the protein kinase C pathway, similar to the situation with genuine endothelial cells. The expression of vWF did not affect the biosynthesis of P-selectin, as deduced from the observation that untransfected and vWF cDNA-transfected T24 cells contained the same amount of P-selectin mRNA. We propose that the biosynthesis of multimeric vWF directs the generation of WPB-like organelles, as evidenced by the sequestering and anchoring of P-selectin into these storage granules. Key Words: von Willebrand factor Ⅲ P-selectin Ⅲ Weibel-Palade bodies Ⅲ protein sorting M ultimeric von Willebrand factor (vWF) is an obligatory glycoprotein for the formation of a hemostatic plug. It connects the platelet to the subendothelium that is exposed on injury of the vessel wall. vWF is synthesized by megakaryocytes and vascular endothelial cells. Endothelial cells display 2 secretory routes for newly synthesized vWF, namely, a constitutive and a regulated pathway. 1 Constitutively secreted vWF is rapidly transported in secretory vesicles toward the plasma membrane. This material consists of vWF dimers and low-molecular-weight multimers. Another portion of the newly synthesized vWF is encountered in specific storage organelles, denoted Weibel-Palade bodies (WPBs). These organelles fuse with the plasma membrane on activation of the protein kinase C signal transduction pathway, followed by release of their contents (regulated secretion). 2,3 vWF routed by this pathway consists of high-molecular-weight multimers that are Ϸ2 orders of magnitude more effective in mediating adhesion of platelets to the injured vessel wall than are vWF dimers or low-molecular-weight multimers. 4 The WPBs are considered to be endothelial cell-specific, rod-shaped, electron-dense storage organelles. 5 Apart from vWF multimers and the vWF propolypeptide, 6 -8 the WPB contains a number of other proteins, namely CD63, a transmembrane glycoprotein that is also present in lysosomal membranes of many cell types 9,10 ; interleukin-8 11 ; tissue plasminogen activator 12 ; and the transmembrane receptor P-selectin (also called GMP-140 or PADGEM). 13,14...

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“…The Doppler crystal was energized by a range-gated pulsed Doppler unit. 12 The signal was range-gated to maximum clarity.…”

Section: Induction Of Ocdusive Arterial Thrombosismentioning

confidence: 99%

“…The protocol for the induction of arterial thrombosis has been fully described previously 12 and is briefly described here. Throughout the procedure, the Doppler signal was observed for cyclic flow reductions (CFRs) or permanent cessation of flow (PCF).…”

Section: Induction Of Ocdusive Arterial Thrombosismentioning

confidence: 99%

Occlusive arterial thrombosis in cynomolgus monkeys with varying plasma concentrations of lipoprotein(a).

Williams

Bellinger

Nichols

et al. 1993

Arterioscler Thromb

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Lipoprotein(a) (Lp[a]) is a newly recognized risk factor for the development of coronary heart disease and stroke in human beings; however, the mechanisms by which Lp(a) increases the risk of coronary heart disease remain unclear. The purpose of this study was to examine the effects of Lp(a) on the occurrence of occlusive arterial thrombosis. Occlusive arterial thrombus formation was examined in 18 cynomolgus monkeys with high plasma Lp(a) concentrations (> 35 mg/dL, n = 6), intermediate Lp(a) concentrations (20-25 mg/dL, n = 6), and low Lp(a) concentrations (< 12 mg/dL, n = 6). A Goldblatt clamp was positioned around the left common carotid artery to produce a stenotic segment, and the artery was pinch-injured with needle holders. A 20-MHz Doppler velocity crystal, placed distal to the stenosis/injury site, was used to detect cyclic flow reductions (indicative of transient thrombosis) or permanent cessation of flow velocity (indicative of more stable occlusive thrombosis). All monkeys with high Lp(a) concentrations developed permanent cessation of flow, whereas only one of six arteries from low-Lp(a) monkeys developed permanent cessation of flow (p < 0.05). Arteries from monkeys with intermediate Lp(a) concentrations developed pronounced cyclic reductions of flow but did not progress to permanent cessation of flow. There were no differences in plasma von Willebrand factor activity among the three groups. Immunohistochemical analysis of the damaged arterial segments indicated incorporation of Lp(a) into the adventitia, media, and intima of arteries from monkeys with low and high plasma Lp(a) concentrations, as well as the presence of an occlusive thrombus in arteries that developed permanent cessation of flow.(ABSTRACT TRUNCATED AT 250 WORDS)

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von Willebrand factor and occlusive arterial thrombosis. A study in normal and von Willebrand's disease pigs with diet-induced hypercholesterolemia and atherosclerosis.

Abstract: The thrombotic response of atherosclerotic arteries to stenosis and Injury was studied In 14 pigs, eight normal and six with von Willebrand's disease (vWD). Atherosclerosis was produced by feeding a 1% to 2% cholesterol diet for 24 weeks.

Cited by 59 publications

References 34 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

Assembly of Multimeric von Willebrand Factor Directs Sorting of P-Selectin

Occlusive arterial thrombosis in cynomolgus monkeys with varying plasma concentrations of lipoprotein(a).

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