IOVS AJP: Advances in Physiology Education
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

(Investigative Ophthalmology and Visual Science. 2004;45:1289-1296.)
© 2004 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.03-0282
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via ISI Web of Science (7)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Akiyama, H.
Right arrow Articles by Kurabayashi, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Akiyama, H.
Right arrow Articles by Kurabayashi, M.

Inhibition of Ocular Angiogenesis by an Adenovirus Carrying the Human von Hippel-Lindau Tumor-Suppressor Gene In Vivo

Hideo Akiyama,1 Toru Tanaka,2 Hirotaka Itakura,1 Hiroyoshi Kanai,2 Tositaka Maeno,2 Hiroshi Doi,2 Miki Yamazaki,2 Kyoichi Takahashi,1 Yasutaka Kimura,1 Shoji Kishi,1 and Masahiko Kurabayashi2

1From the Department of Ophthalmology, and the 2Second Department of Internal Medicine, Gunma University School of Medicine, Gunma, Japan.

PURPOSE. The purpose of this study was to investigate the effect of the von Hippel-Lindau (VHL) protein on VEGF gene expression in vitro and to determine whether adenovirus-mediated VHL intraocular gene transfer inhibits the development of angiogenesis in a monkey model of multiple branch retinal vein occlusion (BRVO).

METHODS. A recombinant adenovirus vector adVHL was constructed to deliver the human VHL gene. Total RNA prepared from various kinds of cells transduced with adLacZ (control) or adVHL under normoxic or hypoxic conditions was subjected to Northern blot analyses. Either adLacZ or adVHL was delivered by preretinal injection in monkeys. The effects of adLacZ or adVHL on ocular neovascularization in laser-induced multiple BRVO was evaluated in color photographs and with fluorescein angiography (FA).

RESULTS. VHL expression in adVHL-transduced cells was confirmed at the transcript and protein levels. VHL overexpression significantly decreased the levels of VEGF transcripts in human aortic endothelial cells (HAECs); retinal pigment epithelium (RPE) cells; and RCC 786-O cells, renal carcinoma cells lacking VHL expression under normoxia. In contrast, VHL had no effect on the hypoxia-mediated increase in VEGF expression in these cells, although basal levels of VEGF expression were substantially reduced. Color photographs and FA revealed that retinal neovascularization and iris rubeosis accompanied by multiple BRVO in a monkey model were obviously suppressed by VHL overexpression. Northern blot analysis and immunostaining for VHL and VEGF indicated that VHL transfer obviously suppressed VEGF gene expression in VHL-transduced tissues such as retina or RPE.

CONCLUSIONS. The results showed that adenovirus expressing VHL led to a significant reduction in VEGF expression in vitro under normoxic or hypoxic conditions. adVHL effectively inhibited angiogenesis in retina and iris in laser-induced multiple BRVO in monkey eyes. These data suggest that gene therapy based on VHL gene delivery has potential in the treatment of human ocular neovascularization.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2004 by the Association for Research in Vision and Ophthalmology