VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain.
VEGF is mitogenic, angiogenic, and a potent mediator of vascular permeability. VEGF causes extravasation of plasma protein in skin bioassays and increases hydraulic conductivity in isolated perfused microvessels. Reduced tissue oxygen tension triggers VEGF expression, and increased protein and mRNA levels for VEGF and its receptors (Flt-1, Flk-1/KDR) occur in the ischemic rat brain. Brain edema, provoked in part by enhanced cerebrovascular permeability, is a major complication in central nervous system pathologies, including head trauma and stroke. The role of VEGF in this pathology has remained elusive because of the lack of a suitable experimental antagonist. We used a novel fusion protein, mFlt(1-3)-IgG, which sequesters murine VEGF, to treat mice exposed to transient cortical ischemia followed by reperfusion. Using high-resolution magnetic resonance imaging, we found a significant reduction in volume of the edematous tissue 1 day after onset of ischemia in mice that received mFlt(1-3)-IgG. 8-12 weeks after treatment, measurements of the resultant infarct size revealed a significant sparing of cortical tissue. Regional cerebral blood flow was unaffected by the administration of mFlt(1-3)-IgG. These results demonstrate that antagonism of VEGF reduces ischemia/reperfusion-related brain edema and injury, implicating VEGF in the pathogenesis of stroke and related disorders.
van Bruggen
N
N
Department of Neuroscience, Genentech Inc., South San Francisco, California 94080, USA. vanbruggen.nick@gene.com
Thibodeaux
H
H
Palmer
J T
JT
Lee
W P
WP
Fu
L
L
Cairns
B
B
Tumas
D
D
Gerlai
R
R
Williams
S P
SP
van Lookeren Campagne
M
M
Ferrara
N
N
D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000473:pathology; D001929:Brain Edema / Q000473:pathology*; D002545:Brain Ischemia / Q000503:physiopathology*; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006651:Histocytochemistry; D007074:Immunoglobulin G / Q000235:genetics; D007274:Injections, Intraperitoneal; D008026:Ligation; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D012039:Regional Blood Flow; D015427:Reperfusion Injury / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D007074:Immunoglobulin G; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1