Positron emission tomography imaging of poststroke angiogenesis

Stroke. 2009 Jan;40(1):270-7. doi: 10.1161/STROKEAHA.108.517474. Epub 2008 Oct 23.

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 approximately 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / analysis
  • Biomarkers / metabolism
  • Bromodeoxyuridine
  • Cell Proliferation
  • Cerebral Arteries / diagnostic imaging*
  • Cerebral Arteries / metabolism
  • Copper Radioisotopes
  • Disease Models, Animal
  • Female
  • Fluorodeoxyglucose F18
  • Infarction, Middle Cerebral Artery / diagnostic imaging*
  • Infarction, Middle Cerebral Artery / physiopathology
  • Kinetics
  • Magnetic Resonance Imaging
  • Neovascularization, Physiologic / physiology*
  • Positron-Emission Tomography / methods*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Vascular Endothelial Growth Factor / analysis*
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Recovery of Function / physiology
  • Stroke / diagnostic imaging*
  • Stroke / physiopathology
  • Vascular Endothelial Growth Factor A / analysis
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Biomarkers
  • Copper Radioisotopes
  • Vascular Endothelial Growth Factor A
  • Fluorodeoxyglucose F18
  • Receptors, Vascular Endothelial Growth Factor
  • Bromodeoxyuridine