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Molecular imaging of activated matrix metalloproteinases in vascular remodeling.

ABSTRACT: Matrix metalloproteinase (MMP) activation plays a key role in vascular remodeling. RP782 is a novel indium (111)In-labeled tracer with specificity for activated MMPs. We hypothesized that RP782 can detect injury-induced vascular remodeling in vivo.Left common carotid artery injury was induced with a guidewire in apolipoprotein E(-/-) mice. Sham surgery was performed on the contralateral artery, which served as control for imaging experiments. Carotid wire injury led to significant hyperplasia and expansive remodeling over a period of 4 weeks. MMP activity, detected by in situ zymography, increased in response to injury and was maximal by 3 to 4 weeks after injury. RP782 (11.1 MBq) was injected intravenously into apolipoprotein E(-/-) mice at 1, 2, 3, and 4 weeks after left carotid injury. MicroSPECT imaging was performed at 2 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 2, 3, and 4 weeks. Increased tracer uptake in the injured artery was confirmed by quantitative autoradiography. Pretreatment with 50-fold excess nonlabeled tracer significantly reduced RP782 uptake in injured carotids, thus demonstrating uptake specificity. Weekly changes in the vessel-wall area closely paralleled and correlated with RP782 uptake (Spearman r=0.95, P=0.001).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.

SUBMITTER: Zhang J

PROVIDER: S-EPMC2637824 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Molecular imaging of activated matrix metalloproteinases in vascular remodeling.

Zhang Jiasheng J Nie Lei L Razavian Mahmoud M Ahmed Masood M Dobrucki Lawrence W LW Asadi Abolfazl A Edwards D Scott DS Azure Michael M Sinusas Albert J AJ Sadeghi Mehran M MM

Circulation 20081020 19

<h4>Background</h4>Matrix metalloproteinase (MMP) activation plays a key role in vascular remodeling. RP782 is a novel indium (111)In-labeled tracer with specificity for activated MMPs. We hypothesized that RP782 can detect injury-induced vascular remodeling in vivo.<h4>Methods and results</h4>Left common carotid artery injury was induced with a guidewire in apolipoprotein E(-/-) mice. Sham surgery was performed on the contralateral artery, which served as control for imaging experiments. Caroti ...[more]

PMID: 18936327

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Project description:PurposeTo evaluate the capability of P947, a magnetic resonance (MR) imaging contrast agent that molecularly targets matrix metalloproteinases (MMPs), to aid detection and imaging of MMPs in atherosclerotic lesions in vivo; its specificity compared with that of P1135; expression and distribution of MMPs in atherosclerotic vessels; and in vivo distribution and molecular localization of fluorescent europium (Eu) P947.Materials and methodsThe Animal Care and Use Committee approved all experiments. P947 was synthesized by attaching a gadolinium chelate (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) to a peptide that specifically binds MMPs. Scrambled form of P947 (P1135) was synthesized by replacing the targeting moiety of P947 with a scrambled peptide lacking the ability to bind MMPs. P947, P1135, and gadoterate meglumine were injected into atherosclerotic apolipoprotein E-deficient and wild-type mice. The aortic MR imaging enhancement produced by the contrast agents was measured at different times and was compared by using one-way analysis of variance. MMP expression was investigated in the aortas by using MMP immunostaining and in situ MMP zymography. A fluorescent form of P947 (Eu-P947) was synthesized to compare the in vivo distribution of the contrast agent (Eu-P947) with specific MMP immunofluorescent staining.ResultsMMP-targeted P947 facilitated a 93% increase (P < .001) in MR image signal intensity (contrast-to-noise ratio [CNR], 17.7 compared with 7.7; P < .001) of atherosclerotic lesions in vivo. Nontargeted P1135 (scrambled P947) provided 33% MR image enhancement (CNR, 10.8), whereas gadoterate meglumine provided 5% (CNR, 6.9). Confocal laser scanning microscopy demonstrated colocalization between fluorescent Eu-P947 and MMPs in atherosclerotic plaques. Eu-P947 was particularly present in the fibrous cap region of plaques.ConclusionP947 improved MR imaging for atherosclerosis through MMP-specific targeting. The results were validated and provide support for further assessment of P947 as a potential tool for the identification of unstable atherosclerosis.

Dataset Information

Molecular imaging of activated matrix metalloproteinases in vascular remodeling.

Publications

Molecular imaging of activated matrix metalloproteinases in vascular remodeling.

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