Abstract 2433: In Vivo Molecular Imaging of Matrix Metalloproteinase Activation in Vascular Remodeling
Matrix metalloproteinase (MMP) activation plays a key role in vascular remodeling, a common feature of a broad spectrum of vasculopathies. RP782 is a novel 111In -labeled tracer with specificity for activated MMP-2, -3, -7, -9, -12 and -13. We hypothesized that RP782 can detect the injury-induced vascular remodeling in vivo. Left common carotid artery injury was induced using a guide wire in apolipoprotein E-null mice. Sham surgery was performed on the contralateral artery, which served as control for imaging experiments. Carotid wire injury led to significant hyperplasia with the vessel wall area increasing from 12752±2822 to 176352±35038 μm2 over a period of 4 weeks (n=4, p<0.01). MMP activity, detected by in-situ zymography, increased in response to injury and was maximal at 3– 4 weeks after injury. RP782 (11.1 MBq) was injected intravenously to apolipoprotein E-null mice at 1, 3, and 4 weeks after left carotid injury. MicroSPECT imaging was performed at 2.5 hours and was followed by CT angiography to localize the carotid arteries. In vivo images revealed focal uptake of RP782 in the injured carotid artery at 3 and 4 weeks after injury. Dose-corrected carotid tracer uptake assessed by quantitative autoradiography was maximal at 3 weeks after injury (362±63, 788±103, and 562±181 mBq/pixel at 1, 3, and 4weekss, n=3 in each group, p<0.05 for 1week vs. 3weeks). Pretreatment with 50-fold excess non-labeled tracer reduced RP782 uptake in injured carotids by 45 folds (n=3, p<0.05), demonstrating uptake specificity. Weekly changes in the carotid artery area closely paralleled and correlated with RP782 uptake (Spearman r=0.9, p<0.05).
In conclusion, injury-induced MMP activation in the vessel wall can be detected by RP782 microSPECT/CT imaging in vivo. RP782 uptake tracks the hyperplastic process in vascular remodeling, and provides an opportunity to track the remodeling process in vivo.