Monitoring of the biological response to murine hindlimb ischemia with 64Cu-labeled vascular endothelial growth factor-121 positron emission tomography

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

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

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 Cu-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 - Cu-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 Cu-VEGF121 positron emission tomography at postoperative day 8, 15, 22, and 29 and correlated with postmortem γ-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. Cu-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 γ-counting (R=0.99). Compared with nonexercised mice, Cu-VEGF121 uptake was increased significantly (P≤0.0001) in exercised mice (at day 15, 22, and 29) and correlated with VEGFR2 levels as obtained by Western blotting (R=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 - Cu-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.

Original languageEnglish (US)
Pages (from-to)915-922
Number of pages8
JournalCirculation
Volume117
Issue number7
DOIs
StatePublished - Feb 2008

Keywords

  • Angiogenesis
  • Arteriosclerosis
  • Exercise
  • Growth substances
  • Imaging
  • Peripheral vascular disease
  • Tomography

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Willmann, J. K., Chen, K., Wang, H., Paulmurugan, R., Rollins, M., Cai, W., Wang, D. S., Chen, I. Y., Gheysens, O., Rodriguez-Porcel, M., Chen, X., & Gambhir, S. S. (2008). Monitoring of the biological response to murine hindlimb ischemia with 64Cu-labeled vascular endothelial growth factor-121 positron emission tomography. Circulation, 117(7), 915-922. https://doi.org/10.1161/CIRCULATIONAHA.107.733220