Targeted in vivo labeling of receptors for vascular endothelial growth factor: approach to identification of ischemic tissue.
BACKGROUND
A method for identifying tissue experiencing hypoxic stress due to atherosclerotic vascular disease would be clinically useful. Vascular endothelial growth factor-121 (VEGF121) is an angiogenic protein secreted in response to hypoxia that binds to VEGF receptors overexpressed by ischemic microvasculature. We tested the hypothesis that VEGF receptors could serve as markers for ischemic tissue and hence provide a target for imaging such tissue with radiolabeled human VEGF121.


RESULTS
A rabbit model of unilateral hindlimb ischemia was created by femoral artery excision (n=14). Control rabbits (n=5) underwent identical surgery without femoral excision. On postoperative day 10, rabbits were intravenously administered 100 microCi of 111In-labeled recombinant human VEGF121, and biodistribution studies and planar imaging were conducted at 3, 24, and 48 hours. On postmortem gamma counting, there was greater accumulation of 111In-labeled VEGF121 in ischemic than in control tissue (P<0.02). Differential uptake of isotope by ischemic muscle was not seen in rabbits injected with 125I-labeled human serum albumin (n=6). Radioactivity imaged in hindlimb regions of interest was significantly higher in ischemic muscle than in sham-operated and contralateral nonoperated hindlimb at 3 hours (P<0.02). Immunohistochemical staining confirmed upregulation of VEGF receptors in ischemic skeletal muscle.


CONCLUSIONS
Identification of the ischemic state via targeted radiolabeling of hypoxia-induced angiogenic receptors is possible. This approach could be useful for monitoring the efficacy of revascularization strategies such as therapeutic angiogenesis.
Lu
Erxiong
E
University of Pittsburgh, Cardiovascular Institute, Department of Bioengineering, Pittsburgh, PA 15213, USA.
Wagner
William R
WR
Schellenberger
Ute
U
Abraham
Judith A
JA
Klibanov
Alexander L
AL
Woulfe
Steven R
SR
Csikari
Melissa M
MM
Fischer
David
D
Schreiner
George F
GF
Brandenburger
Gary H
GH
Villanueva
Flordeliza S
FS
D000818:Animals; D001667:Binding, Competitive; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000493:pharmacokinetics; D005263:Femoral Artery / Q000503:physiopathology; D006614:Hindlimb / Q000098:blood supply* / Q000000981:diagnostic imaging; D007150:Immunohistochemistry; D007205:Indium Radioisotopes; D036341:Intercellular Signaling Peptides and Proteins / Q000493:pharmacokinetics; D007511:Ischemia / Q000000981:diagnostic imaging* / Q000473:pathology / Q000503:physiopathology*; D008222:Lymphokines / Q000493:pharmacokinetics; D008657:Metabolic Clearance Rate; D018482:Muscle, Skeletal / Q000098:blood supply / Q000000981:diagnostic imaging / Q000503:physiopathology; D011237:Predictive Value of Tests; D011817:Rabbits; D011877:Radionuclide Imaging; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D012588:Scintillation Counting; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D007205:Indium Radioisotopes; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D040262:Receptors, Vascular Endothelial Growth Factor