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1 Division of Hypertension and Vascular Research, Henry Ford Health System, Detroit, MI, USA
* To whom correspondence should be addressed. E-mail: ppagano1{at}hfhs.org.
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. For this purpose, we designed a novel replication-deficient adenovirus containing a fibroblast-active promoter driving expression of NADPH oxidase inhibitory sequence gp91ds (AdPDGF
rec-gp91ds/eGFP). First, we characterized the specificity of this promoter using pPDGFrec-luciferase by showing induction of luciferase in cultured rat aortic fibroblasts but not in vascular smooth muscle cells. Second, we observed expression of both gp91ds and reporter gene in fibroblasts after infection with Ad-PDGFrec-gp91ds/eGFP using reverse transcriptase polymerase chain reaction. We then delivered Ad-PDGFrec-gp91ds/eGFP to the adventitia of the rat common carotid artery (CCA), using Ad-CMV-eGFP as a control. Immunohistochemistry confirmed localized delivery of the inhibitor to the adventitia. After CCAs were injured with an embolectomy catheter, we observed a significant increase in neointimal to medial area ratio in control CCAs, which was significantly attenuated in CCAs treated with gp91ds-expressing virus. In a second group of rats, we detected a 10-fold increase in distension-stimulated O2- that 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 the development of neointimal hyperplasia.
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