Positron Emission Tomography Imaging of Poststroke Angiogenesis

Abstract

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, 18 F-FDG PET, and 64 Cu-DOTA-VEGF 121 PET scans. Several control experiments were performed to confirm the VEGFR specificity of 64 Cu-DOTA-VEGF 121 uptake in the stroke border zone. VEGFR, BrdU, lectin staining, and 125 I-VEGF 165 autoradiography on stroke brain tissue slices were performed to validate the in vivo findings. Results— T2-weighed MRI correlated with the “cold spot” on 18 F-FDG PET for rats undergoing distal middle cerebral artery occlusion surgery. The 64 Cu-DOTA-VEGF 121 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 64 Cu-DOTA-VEGF 121 uptake was confirmed by significantly lower uptake of 64 Cu-DOTA-VEGF mutant in vivo and intense 125 I-VEGF 165 uptake ex vivo in the stroke border zone. No appreciable uptake of 64 Cu-DOTA-VEGF 121 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.