VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain.
VEGF is a secreted mitogen associated with angiogenesis and is also a potent vascular permeability factor. The biological role of VEGF in the ischemic brain remains unknown. This study was undertaken to investigate whether VEGF enhances cerebral microvascular perfusion and increases blood-brain barrier (BBB) leakage in the ischemic brain. Using magnetic resonance imaging (MRI), three-dimensional laser-scanning confocal microscope, and functional neurological tests, we measured the effects of administrating recombinant human VEGF(165) (rhVEGF(165)) on angiogenesis, functional neurological outcome, and BBB leakage in a rat model of focal cerebral embolic ischemia. Late (48 hours) administration of rhVEGF(165) to the ischemic rats enhanced angiogenesis in the ischemic penumbra and significantly improved neurological recovery. However, early postischemic (1 hour) administration of rhVEGF(165) to ischemic rats significantly increased BBB leakage, hemorrhagic transformation, and ischemic lesions. Administration of rhVEGF(165) to ischemic rats did not change BBB leakage and cerebral plasma perfusion in the contralateral hemisphere. Our results indicate that VEGF can markedly enhance angiogenesis in the ischemic brain and reduce neurological deficits during stroke recovery and that inhibition of VEGF at the acute stage of stroke may reduce the BBB permeability and the risk of hemorrhagic transformation after focal cerebral ischemia.
Zhang
Z G
ZG
Department of Neurology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, USA.
Zhang
L
L
Jiang
Q
Q
Zhang
R
R
Davies
K
K
Powers
C
C
Bruggen
N v
Nv
Chopp
M
M
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002545:Brain Ischemia / Q000503:physiopathology*; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted; D008222:Lymphokines / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000139:chemically induced*; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow; D020521:Stroke / Q000188:drug therapy*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors