VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia.
Vascular endothelial growth factor (VEGF) is an angiogenic protein with therapeutic potential in ischemic disorders, including stroke. VEGF confers neuroprotection and promotes neurogenesis and cerebral angiogenesis, but the manner in which these effects may interact in the ischemic brain is poorly understood. We produced focal cerebral ischemia by middle cerebral artery occlusion for 90 minutes in the adult rat brain and measured infarct size, neurological function, BrdU labeling of neuroproliferative zones, and vWF-immunoreactive vascular profiles, without and with intracerebroventricular administration of VEGF on days 1-3 of reperfusion. VEGF reduced infarct size, improved neurological performance, enhanced the delayed survival of newborn neurons in the dentate gyrus and subventricular zone, and stimulated angiogenesis in the striatal ischemic penumbra, but not the dentate gyrus. We conclude that in the ischemic brain VEGF exerts an acute neuroprotective effect, as well as longer latency effects on survival of new neurons and on angiogenesis, and that these effects appear to operate independently. VEGF may, therefore, improve histological and functional outcome from stroke through multiple mechanisms.
Sun
Yunjuan
Y
Buck Institute for Age Research, Novato, California 94945, USA.
Jin
Kunlin
K
Xie
Lin
L
Childs
Jocelyn
J
Mao
Xiao Ou
XO
Logvinova
Anna
A
Greenberg
David A
DA
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002544:Cerebral Infarction / Q000188:drug therapy / Q000473:pathology; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008222:Lymphokines / Q000494:pharmacology*; D008297:Male; D009389:Neovascularization, Pathologic / Q000139:chemically induced*; D009416:Nerve Regeneration / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014841:von Willebrand Factor / Q000378:metabolism
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014841:von Willebrand Factor; D001973:Bromodeoxyuridine