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(Stroke. 2009;40:270.)
© 2009 American Heart Association, Inc.

Original Contributions

Positron Emission Tomography Imaging of Poststroke Angiogenesis

Weibo Cai, PhD; Raphael Guzman, MD; Andrew R. Hsu, BS; Hui Wang, PhD; Kai Chen, PhD; Guohua Sun, MD, PhD; Atul Gera, BS; Raymond Choi, BS; Tonya Bliss, PhD; Lina He, MD; Zi-Bo Li, PhD; Anne-Lise D. Maag, BS; Nobutaka Hori, MD, PhD; Heng Zhao, PhD; Michael Moseley, PhD; Gary K. Steinberg, MD, PhD Xiaoyuan Chen, PhD

From The Molecular Imaging Program at Stanford (W.C., A.R.H, H.W., L.H., K.C., Z-B.L., M.M., X.C.), Department of Radiology, Stanford University, Calif; Departments of Radiology and Medical Physics (W.C.), University of Wisconsin–Madison, Wis; Department of Neurosurgery (R.G., G.S., A.G., R.C., T.B., A-L.D.M., N.H., H.Z., G.K.S.), Stanford University, Calif.

Correspondence to Xiaoyuan Chen, PhD, The Molecular Imaging Program at Stanford, Department of Radiology, Stanford University, Stanford, CA. E-mail shawchen{at}stanford.edu

Background and Purpose— Vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) play important roles during neurovascular repair after stroke. In this study, we imaged VEGFR expression with positron emission tomography (PET) to noninvasively analyze poststroke angiogenesis.

Methods— Female Sprague-Dawley rats after distal middle cerebral artery occlusion surgery were subjected to weekly MRI, ¹⁸F-FDG PET, and ⁶⁴Cu-DOTA-VEGF₁₂₁ PET scans. Several control experiments were performed to confirm the VEGFR specificity of ⁶⁴Cu-DOTA-VEGF₁₂₁ uptake in the stroke border zone. VEGFR, BrdU, lectin staining, and ¹²⁵I-VEGF₁₆₅ autoradiography on stroke brain tissue slices were performed to validate the in vivo findings.

Results— T2-weighed MRI correlated with the "cold spot" on ¹⁸F-FDG PET for rats undergoing distal middle cerebral artery occlusion surgery. The ⁶⁴Cu-DOTA-VEGF₁₂₁ uptake in the stroke border zone peaked at 10 days after surgery, indicating neovascularization as confirmed by histology (VEGFR-2, BrdU, and lectin staining). VEGFR specificity of ⁶⁴Cu-DOTA-VEGF₁₂₁ uptake was confirmed by significantly lower uptake of ⁶⁴Cu-DOTA-VEGF_mutant in vivo and intense ¹²⁵I-VEGF₁₆₅ uptake ex vivo in the stroke border zone. No appreciable uptake of ⁶⁴Cu-DOTA-VEGF₁₂₁ was observed in the brain of sham-operated rats.

Conclusions— For the first time to our knowledge, we successfully evaluated the VEGFR expression kinetics noninvasively in a rat stroke model. In vivo imaging of VEGFR expression could become a significant clinical tool to plan and monitor therapies aimed at improving poststroke angiogenesis.

Key Words: positron emission tomography • stroke • vascular endothelial growth factor receptor