Molecular Imaging of Angiogenesis in Early-Stage Atherosclerosis With α v β 3 -Integrin–Targeted Nanoparticles

Abstract

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. Methods and Results— Atherosclerosis was induced in New Zealand White rabbits fed 1% cholesterol for ≈80 days. α _v β ₃ -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 α _v β ₃ -targeted, paramagnetic nanoparticles. Pretreatment of atherosclerotic rabbits with α _v β ₃ -targeted, nonparamagnetic nanoparticles competitively blocked specific contrast enhancement of the α _v β ₃ -targeted paramagnetic agent. MRI revealed a pattern of increased α _v β ₃ -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.