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Noninvasive Monitoring of the Development and Treatment Response of Ischemic Hindlimb by Targeting Matrix Metalloproteinase-2 (MMP-2)
28 Pages Posted: 14 Jun 2019
More...Abstract
Critical limb ischemia (CLI) is a common cause of high vascular morbidity and mortality. Monitoring the development and treatment response of hindlimb ischemia (HI) in an animal model enables us to better understand the pathological mechanisms underlying CLI, as well as evaluate the efficacy of novel therapeutic approaches. Matrix metalloproteinase (MMP) activity is essential for remodeling of ischemic tissue including extracellular matrix degradation and angiogenesis. Herein, a mouse HI model was established and subjected to noninvasive optical imaging with a novel and ultra-sensitive matrix metalloproteinase (MMP) activatable probe, termed MMP-P12, for analyzing the development and treatment response of HI. Our results show that the angiogenesis development during HI was well correlated with the MMP-2 activity alternation as examined by Western blot, histological staining and MMP-P12 fluorescent signal recovery. Moreover, vascular endothelial growth factor (VEGF) mediated HI treatment was also monitored by MMP-P12. An up-regulated MMP-2 expression and enhancement of angiogenesis were observed after VEGF treatment, which peaked at 7 days after treatment. Overall, our results presented that MMP-2 plays an important role in monitoring of angiogenesis during HI development and therapy. Application of MMP-P12 to visualize MMP-2 activity alternation can serve as a promising noninvasive optical imaging strategy to monitor angiogenesis and its response to therapy in CLI.
Funding Statement: This study was supported by the National Nature Science Foundation of China (81400366, 81500183 and 81800808) and Shaanxi Natural Science Foundation (2016JM8012). None of these funding sources had any role in writing the manuscript nor the decision to submit for publication.
Declaration of Interests: The authors declare no competing financial interest.
Ethics Approval Statement: All animal models were prepared under a protocol approved by the National Institutes of Health, Clinical Center Animal Care and Use Committee (ACUC).
Keywords: hindlimb ischemia, angiogenesis, MMP-2, optical imaging, activatable probe
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