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1Division of Vascular Surgery and 2Hypertension and Vascular Research Division, Henry Ford Health System, Detroit, Michigan; and 3Gene Transfer Vector Core, University of Iowa, Iowa City, Iowa
Submitted 30 April 2004 ; accepted in final form 16 September 2004
Vascular stretch induces NADPH oxidase-derived superoxide anion (O2–), which has been implicated in hypertrophy and cell proliferation. We hypothesized that targeted delivery of an NADPH oxidase inhibitor to the adventitia would reduce stretch-induced vascular O2– and attenuate neointima formation. We designed a novel replication-deficient adenovirus containing a fibroblast-active promoter driving expression of NADPH oxidase inhibitory sequence gp91ds (Ad-PDGF
R-gp91ds/eGFP). 1) We characterized the specificity of this promoter using pPDGFR-luciferase by showing induction of luciferase in cultured rat aortic fibroblasts but not in vascular smooth muscle cells. 2) Using RT-PCR, we observed expression of gp91ds and the reporter gene in fibroblasts after infection with Ad-PDGFR-gp91ds/eGFP. 3) Using Ad-CMV-eGFP as a control, we delivered Ad-PDGFR-gp91ds/eGFP to the adventitia of the rat common carotid artery (CCA). Immunohistochemistry confirmed localized delivery of the inhibitor to the adventitia. After CCAs were injured with an embolectomy catheter, we observed a significant increase in neointima-to-media area ratio in control CCAs, which was significantly attenuated in CCAs treated with the gp91ds-expressing virus. In a second group of rats, we detected a 10-fold increase in distension-stimulated O2–, which was significantly reduced in CCAs infected with gp91ds-expressing virus. These data demonstrate that localized adventitial delivery of an NADPH oxidase inhibitor is effective in reducing overall vascular O2– and neointima formation, suggesting that adventitial NADPH oxidase plays a functional role in development of neointimal hyperplasia.
superoxide; adventitia; stenosis
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