Recombinant adeno-associated viral vector encoding human VEGF165 induces neomicrovessel formation in the adult mouse brain.
Delivery of therapeutic genes represents a fascinating possibility to accelerate injury-repairing process in tissues that are otherwise difficult to treat, such as cerebral ischemia. Current studies indicate that gene transfer-induced focal angiogenesis in the brain may provide an important therapeutic strategy. In the present study, we reported the efficacy of induction of angiogenesis with an adeno-associated virus (AAV) vector expressing the 165 amino acid isoform of vascular endothelial growth factor (VEGF165). We found AAV serotype 1 has more efficiency in transduction of the brain tissue than AAV serotype 2. Quantitative vessel counting showed that microvessels in AAV-VEGF transduced mice significantly increased from 1 week up to 12 weeks compared to the control groups (AAV-VEGF: 316+/-58 vs. AAV-lacZ: 180+/-34 and saline: 152+/-35 vessels/mm2, at 6 weeks, p<0.05). Proliferating cell nuclear antigen (PCNA) staining confirmed these microvessels were actively proliferating. Double-labeled fluorescence staining demonstrated that neurons, astrocytes, and endothelial cells could express VEGF following AAV-VEGF gene transfer. AAV vectors did not elicit a detectable inflammatory response, cell loss or neuronal damage. Our data underline the importance of angiogenesis in the brain tissue and indicate that VEGF gene transfer might present a valuable approach to treat brain ischemic disorders.
Shen
Fanxia
F
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94110, USA.
Su
Hua
H
Liu
Weizhong
W
Kan
Yuet W
YW
Young
William L
WL
Yang
Guo-Yuan
GY
D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000166:cytology / Q000378:metabolism; D002545:Brain Ischemia / Q000628:therapy; D049109:Cell Proliferation; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D007763:Lac Operon; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018919:Neovascularization, Physiologic / Q000235:genetics*; D012703:Serotyping; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000627:therapeutic use
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A