title: In vivo transfer of human hepatocyte growth factor gene accelerates re-endothelialization and inhibits neointimal formation after balloon injury in rat model.
abstract: Although most therapeutic strategies to prevent restenosis are designed to inhibit vascular smooth muscle cell (VSMC) proliferation directly, VSMC proliferation might be indirectly inhibited by re-endothelialization, as endothelial cells secrete antiproliferative and antithrombotic substances. We hypothesized that application of an endothelium-specific growth factor to balloon-injured arteries could accelerate re-endothelialization, thereby attenuating intimal hyperplasia. In this study, we investigated in vivo gene transfer of human HGF that exclusively stimulated endothelial cells without replication of VSMC growth into injured vessels. Transfection of human HGF gene into rat balloon-injured carotid artery resulted in significant inhibition of neointimal formation up to at least 8 weeks after transfection, accompanied by detection of human immunoreactive HGF. Induction of re-endothelialization induced by overexpression of human HGF gene transfer into balloon-injured vessels is supported by several lines of evidence: (1) Administration of HGF vector. but not control vector, markedly inhibited neointimal formation, accompanied by a significant increase in vascular human and rat HGF concentrations. (2) Planimetric analysis demonstrated a significant increase in re-endothelialized area in arteries transfected with human HGF vector. (3) Induction of NO content in balloon-injured vessels transfected with human HGF vector was observed in accordance with the recovery of endothelial vasodilator properties in response to acetylcholine. As endogenous HGF expression in balloon-injured vessels was significantly decreased as compared with normal vessels, the present study demonstrated the successful inhibition of neointimal formation by transfection of human HGF gene as 'cytokine supplement therapy' in a rat balloon injury model.
authors.affiliation: Division of Gene Therapy Science, Osaka University Medical School, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hayashi
authors.forename: S
authors.initials: S
authors.lastname: Nakamura
authors.forename: R
authors.initials: R
authors.lastname: Morishita
authors.forename: A
authors.initials: A
authors.lastname: Moriguchi
authors.forename: M
authors.initials: M
authors.lastname: Aoki
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.forename: Y
authors.initials: Y
authors.lastname: Kaneda
authors.forename: N
authors.initials: N
authors.lastname: Sakai
authors.forename: T
authors.initials: T
authors.lastname: Ogihara
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D020212:Carotid Artery Injuries / Q000628:therapy; D016893:Carotid Stenosis / Q000628:therapy*; D002404:Catheterization / Q000009:adverse effects; D004730:Endothelium, Vascular / Q000254:growth & development* / Q000293:injuries / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000032:analysis / Q000235:genetics*; D006801:Humans; D008297:Male; D009389:Neovascularization, Pathologic; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D018108:Respirovirus / Q000235:genetics; D014162:Transfection / Q000379:methods*; D019076:Transgenes; D014665:Vasodilator Agents / Q000494:pharmacology; D022701:Virosomes
chemical_list: D014665:Vasodilator Agents; D022701:Virosomes; D009569:Nitric Oxide; D017228:Hepatocyte Growth Factor; D000109:Acetylcholine