Molecular imaging of vulnerable plaques in rabbits using contrast-enhanced ultrasound targeting to vascular endothelial growth factor receptor-2

Abstract

Purpose: Increased neovascularization has been identified as a feature of atherosclerotic plaque vulnerability and can be traced by microbubble ultrasound contrast agents (UCA). We investigated the relationship between retention of a vascular endothelial growth factor receptor 2 (VEGFR-2) targeted UCA and VEGFR-2 expression in a vulnerable plaque model in rabbits.

Methods: Microbubbles targeting to VEGFR-2 were prepared by conjugation of biotinylated microbubbles with biotinylated VEGFR-2 antibody via streptavidin. Vulnerability was created by delivering recombinant p53 adenovirus to atherosclerotic plaques obtained in abdominal aorta by a high cholesterol diet and balloon endothelial injury. Twelve week later, the average video intensity of pre- and postcontrast ultrasound images was measured. VEGFR-2 expression and vascular density were quantified by immunohistochemical staining.

Results: Retention of targeted UCA in plaques was higher than that of nontargeted UCA (144 ± 18 dB versus 107 ± 9 dB; Z= -3.984, p = 0.000). VEGFR-2 expression was correlated with video intensity of targeted (r(2) = 0.78, p = 0.001), but not of nontargeted, UCA (r(2) = 0.17, p ≥ 0.05).

Conclusions: The magnitude of the sonographic signal from retained VEGFR-2 targeted UCA correlates with VEGFR-2 expression. These results validate the use of targeted UCA for sonographic imaging of vulnerable abdominal artery plaques in rabbits.