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Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner.

ABSTRACT: Rupture of a vulnerable atherosclerotic plaque causes thrombus formation and precipitates cardiovascular diseases. In addition to the thrombogenic content of a plaque, also the hemodynamic microenvironment plays a major role in thrombus formation. How the altered hemodynamics around a plaque promote pathological thrombus formation is not well understood. In this study, we provide evidence that plaque geometries result in fluid mechanical conditions that promote platelet aggregation and thrombus formation by increased accumulation and activity of von Willebrand factor (vWF) at poststenotic sites. Resonant-scanning multiphoton microscopy revealed that in vivo arterial stenosis of a damaged carotid artery markedly increased platelet aggregate formation in the stenotic outlet region. Complementary in vitro studies using microfluidic stenotic chambers, designed to mimic the flow conditions in a stenotic artery, showed enhanced platelet aggregation in the stenotic outlet region at 60-80% channel occlusion over a range of input wall shear rates. The poststenotic thrombus formation was critically dependent on bloodborne vWF and autocrine platelet stimulation. In stenotic chambers containing endothelial cells, flow provoked increased endothelial vWF secretion in the stenotic outlet region, contributing to exacerbated platelet aggregation. Taken together, this study identifies a role for the shear-sensitive protein vWF in transducing hemodynamic forces that are present around a stenosis to a prothrombogenic microenvironment resulting in spatially confined and exacerbated platelet aggregation in the stenosis outlet region. The developed stenotic microfluidic chamber offers a realistic platform for in vitro evaluation of shear-dependent thrombus formation in the setting of atherosclerosis.

SUBMITTER: Westein E

PROVIDER: S-EPMC3557050 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner.

Westein Erik E van der Meer Andries D AD Kuijpers Marijke J E MJ Frimat Jean-Philippe JP van den Berg Albert A Heemskerk Johan W M JW

Proceedings of the National Academy of Sciences of the United States of America 20130103 4

Rupture of a vulnerable atherosclerotic plaque causes thrombus formation and precipitates cardiovascular diseases. In addition to the thrombogenic content of a plaque, also the hemodynamic microenvironment plays a major role in thrombus formation. How the altered hemodynamics around a plaque promote pathological thrombus formation is not well understood. In this study, we provide evidence that plaque geometries result in fluid mechanical conditions that promote platelet aggregation and thrombus ...[more]

PMID: 23288905

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Project description:We hypothesized that noninvasive molecular imaging of activated von Willebrand factor (vWF) on the vascular endothelium could be used to detect a high-risk atherosclerotic phenotype.Platelet-endothelial interactions have been linked to increased inflammatory activation and prothrombotic state in atherosclerosis. These interactions are mediated, in part, by platelet glycoprotein (GP) Ib?, suggesting that dysregulated endothelial vWF is a marker for high-risk atherosclerotic disease.Microbubbles targeted to activated vWF were prepared by surface conjugation of recombinant GPIb?. Flow-chamber studies were used to evaluate attachment of targeted microbubbles to immobile platelet aggregates bearing activated vWF. Contrast-enhanced ultrasound (CEU) molecular imaging of the aorta from mice was performed: 1) ex vivo after focal crush injury and blood perfusion; and 2) in vivo in mice with advanced atherosclerosis produced by deletion of the low-density lipoprotein receptor and ApoBec-1 editing peptide (LDLR(-/-)/ApoBec-1(-/-)).In flow-chamber studies, tracer attachment to vWF was >10-fold greater for microbubbles bearing GPIb? compared with control microbubbles (p < 0.01). In the ex vivo aortic injury model, CEU signal enhancement for vWF-targeted microbubbles occurred primarily at the injury site and was 4-fold greater than at noninjured sites (p < 0.05). In LDLR(-/-)/ApoBec-1(-/-) mice, inflammatory cell infiltrates and dense vWF expression on the intact endothelium were seen in regions of severe plaque formation. Scanning electron microscopy demonstrated widespread platelet-endothelial interaction and only few sites of endothelial erosion. On CEU, signal enhancement for vWF-targeted microbubbles was approximately 4-fold greater (p < 0.05) in LDLR(-/-)/ApoBec-1(-/-) compared with wild-type mice. En face aortic microscopy demonstrated regions where platelet adhesion and microbubble attachment colocalized.Molecular imaging using GPIb? as a targeting moiety can detect the presence of activated vWF on the vascular endothelium. This strategy may provide a means to noninvasively detect an advanced prothrombotic and inflammatory phenotype in atherosclerotic disease.

Dataset Information

Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner.

Publications

Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner.

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