Molecular imaging of activated von Willebrand factor to detect high-risk atherosclerotic phenotype.

Owen McCarty, Robert B. Conley, Weihui Shentu, Garth W. Tormoen, Daogang Zha, Aris Xie, Qi Yue, Yan Zhao, Chad Carr, Todd Belcik, Douglas R. Keene, Philip G. de Groot, Jonathan Lindner

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Abstract

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) Ibα, 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 GPIbα. 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 GPIbα 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 GPIbα 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.

Original languageEnglish (US)
Pages (from-to)947-955
Number of pages9
JournalJACC. Cardiovascular imaging
Volume3
Issue number9
StatePublished - Sep 2010

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Molecular Imaging
von Willebrand Factor
Microbubbles
Phenotype
Blood Platelets
Vascular Endothelium
Atherosclerosis
Platelet Glycoprotein GPIb-IX Complex
Platelet Membrane Glycoproteins
LDL Receptors
Wounds and Injuries
Electron Scanning Microscopy
Endothelium
Aorta
Microscopy
Ultrasonography
Perfusion
Peptides

ASJC Scopus subject areas

  • Medicine(all)

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Molecular imaging of activated von Willebrand factor to detect high-risk atherosclerotic phenotype. / McCarty, Owen; Conley, Robert B.; Shentu, Weihui; Tormoen, Garth W.; Zha, Daogang; Xie, Aris; Yue, Qi; Zhao, Yan; Carr, Chad; Belcik, Todd; Keene, Douglas R.; de Groot, Philip G.; Lindner, Jonathan.

In: JACC. Cardiovascular imaging, Vol. 3, No. 9, 09.2010, p. 947-955.

Research output: Contribution to journalArticle

McCarty, O, Conley, RB, Shentu, W, Tormoen, GW, Zha, D, Xie, A, Yue, Q, Zhao, Y, Carr, C, Belcik, T, Keene, DR, de Groot, PG & Lindner, J 2010, 'Molecular imaging of activated von Willebrand factor to detect high-risk atherosclerotic phenotype.', JACC. Cardiovascular imaging, vol. 3, no. 9, pp. 947-955.
McCarty, Owen ; Conley, Robert B. ; Shentu, Weihui ; Tormoen, Garth W. ; Zha, Daogang ; Xie, Aris ; Yue, Qi ; Zhao, Yan ; Carr, Chad ; Belcik, Todd ; Keene, Douglas R. ; de Groot, Philip G. ; Lindner, Jonathan. / Molecular imaging of activated von Willebrand factor to detect high-risk atherosclerotic phenotype. In: JACC. Cardiovascular imaging. 2010 ; Vol. 3, No. 9. pp. 947-955.
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AU - Zha, Daogang

AU - Xie, Aris

AU - Yue, Qi

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