Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v)beta3-integrin-targeted nanoparticles.
BACKGROUND
Angiogenesis is a critical feature of plaque development in atherosclerosis and might play a key role in both the initiation and later rupture of plaques that lead to myocardial infarction and stroke. The precursory molecular or cellular events that initiate plaque growth and that ultimately contribute to plaque instability, however, cannot be detected directly with any current diagnostic modality.


RESULTS
Atherosclerosis was induced in New Zealand White rabbits fed 1% cholesterol for approximately 80 days. alpha(v)beta3-Integrin-targeted, paramagnetic nanoparticles were injected intravenously and provided specific detection of the neovasculature within 2 hours by routine magnetic resonance imaging (MRI) at a clinically relevant field strength (1.5 T). Increased angiogenesis was detected as a 47+/-5% enhancement in MRI signal averaged throughout the abdominal aortic wall among rabbits that received alpha(v)beta3-targeted, paramagnetic nanoparticles. Pretreatment of atherosclerotic rabbits with alpha(v)beta3-targeted, nonparamagnetic nanoparticles competitively blocked specific contrast enhancement of the alpha(v)beta3-targeted paramagnetic agent. MRI revealed a pattern of increased alpha(v)beta3-integrin distribution within the atherosclerotic wall that was spatially heterogeneous along both transverse and longitudinal planes of the abdominal aorta. Histology and immunohistochemistry confirmed marked proliferation of angiogenic vessels within the aortic adventitia, coincident with prominent, neointimal proliferation among cholesterol-fed, atherosclerotic rabbits in comparison with sparse incidence of neovasculature in the control animals.


CONCLUSIONS
This molecular imaging approach might provide a method for defining the burden and evolution of atherosclerosis in susceptible individuals as well as responsiveness of individual patients to antiatherosclerotic therapies.
Winter
Patrick M
PM
Cardiovascular Magnetic Resonance Laboratories, Department of Medicine, Washington University School of Medicine, St Louis, Mo 63110, USA.
Morawski
Anne M
AM
Caruthers
Shelton D
SD
Fuhrhop
Ralph W
RW
Zhang
Huiying
H
Williams
Todd A
TA
Allen
John S
JS
Lacy
Elizabeth K
EK
Robertson
J David
JD
Lanza
Gregory M
GM
Wickline
Samuel A
SA
D000818:Animals; D001011:Aorta / Q000473:pathology; D001161:Arteriosclerosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D002791:Cholesterol, Dietary; D003287:Contrast Media / Q000008:administration & dosage; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D039302:Integrin alphaVbeta3 / Q000032:analysis / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D009389:Neovascularization, Pathologic / Q000473:pathology*; D010316:Particle Size; D011817:Rabbits; D012680:Sensitivity and Specificity
D002791:Cholesterol, Dietary; D003287:Contrast Media; D039302:Integrin alphaVbeta3