Gene therapy inhibiting neointimal vascular lesion: In vivo transfer of endothelial cell nitric oxide synthase gene

Heiko E. Von Der Leyen, Gary H. Gibbons, Ryuichi Morishita, Neil P. Lewis, Lunan Zhang, Masatoshi Nakajima, Yasufumi Kaneda, John P. Cooke, Victor J. Dzau

Research output: Contribution to journalArticle

662 Scopus citations

Abstract

It is postulated that vascular disease involves a disturbance in the homeostatic balance of factors regulating vascular tone and structure. Recent developments in gene transfer techniques have emerged as an exciting therapeutic option to treat vascular disease. Several studies have established the feasibility of direct in vivo gene transfer into the vasculature by using reporter genes such as β-galactosidase or luciferase. To date no study has documented therapeutic effects with in vivo gene transfer of a cDNA encoding a functional enzyme. This study tests the hypothesis that endothelium-derived nitric oxide is an endogenous inhibitor of vascular lesion formation. After denudation by balloon injury of the endothelium of rat carotid arteries, we restored endothelial cell nitric oxide synthase (ec-NOS) expression in the vessel wall by using the highly efficient Sendai virus/liposome in vivo gene transfer technique. ec-NOS gene transfection not only restored NO production to levels seen in normal untreated vessels but also increased vascular reactivity of the injured vessel. Neointima formation at day 14 after balloon injury was inhibited by 70%. These findings provide direct evidence that NO is an endogenous inhibitor of vascular lesion formation in vivo (by inhibiting smooth muscle cell proliferation and migration) and suggest the possibility of ec-NOS transfection as a potential therapeutic approach to treat neointimal hyperplasia.

Original languageEnglish (US)
Pages (from-to)1137-1141
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number4
DOIs
StatePublished - Feb 14 1995

ASJC Scopus subject areas

  • General

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