Document Detail

Monitoring of the biological response to murine hindlimb ischemia with 64Cu-labeled vascular endothelial growth factor-121 positron emission tomography.
MedLine Citation:
PMID:  18250264     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Vascular endothelial growth factor-121 (VEGF121), an angiogenic protein secreted in response to hypoxic stress, binds to VEGF receptors (VEGFRs) overexpressed on vessels of ischemic tissue. The purpose of this study was to evaluate 64Cu-VEGF121 positron emission tomography for noninvasive spatial, temporal, and quantitative monitoring of VEGFR2 expression in a murine model of hindlimb ischemia with and without treadmill exercise training.
METHODS AND RESULTS: 64Cu-labeled VEGF121 and a VEGF mutant were tested for VEGFR2 binding specificity in cell culture. Mice (n=58) underwent unilateral ligation of the femoral artery, and postoperative tissue ischemia was assessed with laser Doppler imaging. Longitudinal VEGFR2 expression in exercised and nonexercised mice was quantified with 64Cu-VEGF121 positron emission tomography at postoperative day 8, 15, 22, and 29 and correlated with postmortem gamma-counting. Hindlimbs were excised for immunohistochemistry, Western blotting, and microvessel density measurements. Compared with the VEGF mutant, VEGF121 showed specific binding to VEGFR2. Perfusion in ischemic hindlimbs fell to 9% of contralateral hindlimb on postoperative day 1 and recovered to 82% on day 29. 64Cu-VEGF121 uptake in ischemic hindlimbs increased significantly (P < 0.001) from a control level of 0.61+/-0.17% ID/g (percentage of injected dose per gram) to 1.62+/-0.35% ID/g at postoperative day 8, gradually decreased over the following 3 weeks (0.59+/-0.14% ID/g at day 29), and correlated with gamma-counting (R2 = 0.99). Compared with nonexercised mice, 64Cu-VEGF121 uptake was increased significantly (P < or = 0.0001) in exercised mice (at day 15, 22, and 29) and correlated with VEGFR2 levels as obtained by Western blotting (R2 = 0.76). Ischemic hindlimb tissue stained positively for VEGFR2. In exercised mice, microvessel density was increased significantly (P<0.001) compared with nonexercised mice.
CONCLUSIONS: 64Cu-VEGF121 positron emission tomography allows longitudinal spatial and quantitative monitoring of VEGFR2 expression in murine hindlimb ischemia and indirectly visualizes enhanced angiogenesis stimulated by treadmill exercise training.
Jürgen K Willmann; Kai Chen; Hui Wang; Ramasamy Paulmurugan; Mark Rollins; Weibo Cai; David S Wang; Ian Y Chen; Olivier Gheysens; Martin Rodriguez-Porcel; Xiaoyuan Chen; Sanjiv S Gambhir
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Publication Detail:
Type:  Evaluation Studies; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-02-04
Journal Detail:
Title:  Circulation     Volume:  117     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-02-20     Completed Date:  2008-03-17     Revised Date:  2014-09-09    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  915-22     Citation Subset:  AIM; IM    
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MeSH Terms
Cells, Cultured / metabolism
Collateral Circulation / physiology*
Copper Radioisotopes / diagnostic use*
Endothelial Cells / cytology
Hindlimb / blood supply*,  radionuclide imaging
Ischemia / radionuclide imaging*,  ultrasonography
Mice, Inbred C57BL
Mutagenesis, Site-Directed
Physical Conditioning, Animal
Positron-Emission Tomography*
Protein Binding
Radiopharmaceuticals / diagnostic use*
Vascular Endothelial Growth Factor A / diagnostic use*,  genetics,  metabolism
Vascular Endothelial Growth Factor Receptor-1 / metabolism
Vascular Endothelial Growth Factor Receptor-2 / metabolism*
Grant Support
Reg. No./Substance:
0/Copper Radioisotopes; 0/Radiopharmaceuticals; 0/VEGFA protein, human; 0/Vascular Endothelial Growth Factor A; EC Endothelial Growth Factor Receptor-1; EC Endothelial Growth Factor Receptor-2

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