Encapsulated vascular endothelial growth factor-secreting cell grafts have neuroprotective and angiogenic effects on focal cerebral ischemia.
OBJECTIVE
The authors evaluated the neuroprotective and angiogenic effects of a continuous and low-dose infusion of vascular endothelial growth factor (VEGF)-165 on cerebral ischemia in rats.


METHODS
The authors introduced VEGF complementary (c)DNA into baby hamster kidney (BHK) cells and established a cell line that produces human VEGF165 (BHK-VEGF). The BHK-VEGF cells and BHK cells that had been transfected with an expression vector that did not contain human VEGF165 cDNA (BHK-control) were encapsulated. Both capsules were implanted into rat striata. Six days after capsule implantation, the right middle cerebral artery (MCA) was occluded. Some animals were killed 24 hours after occlusion to measure the volume of the resulting infarct and to perform immunohistochemical studies. Other animals were used for subsequent behavioral studies 1, 7, and 14 days after MCA occlusion. The encapsulated BHK-VEGF cell grafts significantly reduced the volume of the infarct and the number of apoptotic cells in the penumbral area when compared with the effect of the BHK-control cell capsule. In addition, angiogenesis and gliogenesis significantly increased in the region around the capsule in animals that received BHK-VEGF cell capsules without an increase in focal cerebral blood flow; this did not occur in animals that received the BHK-control cell capsule. In behavioral studies rats that received the BHK-VEGF cell capsule displayed significant recovery while participating in the accelerating rotarod test after stroke.


CONCLUSIONS
Continuous intracerebral administration of low-dose VEGF165 through encapsulated grafts of VEGF-producing cells produces neuroprotective and angiogenic effects. These effects improve subsequent motor function.
Yano
Akimasa
A
Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan. a-yano@jd5.so-net.ne.jp
Shingo
Tetsuro
T
Takeuchi
Akira
A
Yasuhara
Takao
T
Kobayashi
Kazuki
K
Takahashi
Kazuya
K
Muraoka
Kenichiro
K
Matsui
Toshihiro
T
Miyoshi
Yasuyuki
Y
Hamada
Hirofumi
H
Date
Isao
I
D000818:Animals; D017690:Cell Transplantation; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000166:cytology; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009457:Neuroglia / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000235:genetics
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A