title: Gene transfer of hepatocyte growth factor to subarachnoid space in cerebral hypoperfusion model.
abstract: Although cerebral hypoperfusion caused by cerebral occlusive disease leads to cerebral ischemic events, an effective treatment has not yet been established. Recently, a novel therapeutic strategy for ischemic disease using angiogenic growth factors to expedite and/or augment collateral artery development has been proposed. Therapeutic angiogenesis might be useful for the treatment of cerebral occlusive disease. Hepatocyte growth factor (HGF) is a potent angiogenic factor, in addition to vascular endothelial growth factor (VEGF), whereas in the nervous system HGF also acts as neurotrophic factor. Therefore, we hypothesized that gene transfer of these angiogenic growth factors could induce angiogenesis, thus providing an effective therapy for cerebral hypoperfusion or stroke. In this study, we employed a highly efficient gene transfer method, the viral envelop (Hemagglutinating Virus of Japan [HVJ]-liposome) method, because we previously documented that beta-galactosidase gene could be transfected into the brain by the HVJ-liposome method. Indeed, we confirmed wide distribution of transgene expression using beta-galactosidase via injection into the subarachnoid space. Of importance, transfection of HGF or VEGF gene into the subarachnoid space 7 days before occlusion induced angiogenesis on the brain surface as assessed by alkaline phosphatase staining (P<0.01). In addition, significant improvement of cerebral blood flow (CBF) was observed by laser Doppler imaging (LDI) 7 days after occlusion (P<0.01). Unexpectedly, transfection of HGF or VEGF gene into the subarachnoid space immediately after occlusion of the bilateral carotid arteries also induced angiogenesis on the brain surface and had a significant protective effect on the impairment of CBF by carotid occlusion (P<0.01). Interestingly, coinjection of recombinant HGF with HGF gene transfer revealed a further increase in CBF (P<0.01). Here, we demonstrated successful therapeutic angiogenesis using HGF or VEGF gene transfer into the subarachnoid space to improve cerebral hypoperfusion, thus providing a new therapeutic strategy for cerebral ischemic disease.
authors.affiliation: Department of Neurosurgery, Gifu University School of Medicine, Gifu, Japan.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Yoshimura
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Hayashi
authors.forename: Jouji
authors.initials: J
authors.lastname: Kokuzawa
authors.forename: Motokuni
authors.initials: M
authors.lastname: Aoki
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogihara
authors.forename: Noboru
authors.initials: N
authors.lastname: Sakai
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000254:growth & development; D001921:Brain / Q000098:blood supply / Q000187:drug effects; D002545:Brain Ischemia / Q000235:genetics / Q000628:therapy*; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008081:Liposomes; D008222:Lymphokines / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics; D013346:Subarachnoid Space; D014162:Transfection / Q000379:methods*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D001616:beta-Galactosidase / Q000008:administration & dosage / Q000235:genetics
chemical_list: D016228:Endothelial Growth Factors; D008081:Liposomes; D008222:Lymphokines; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D017228:Hepatocyte Growth Factor; D001616:beta-Galactosidase