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Adventitial delivery of dominant-negative p67^phox attenuates neointimal hyperplasia of the rat carotid artery

¹Hypertension and Vascular Research Division, ²Division of Vascular Surgery, and ³Biostatistics and Research Epidemiology Department, Henry Ford Health System, Detroit, Michigan; and ⁴Myocardial Biology Unit, Boston University Medical Center, Boston, Massachusetts

Submitted 27 June 2005 ; accepted in final form 31 October 2005

Several essential components of NADPH oxidase, including p22^phox, gp91^phox (nox2) and its homologs nox1 and nox4, p47^phox, p67^phox, and rac1, are present in the vasculature. We previously reported that p67^phox is essential for adventitial fibroblast NADPH oxidase O₂^– production. Thus we postulated that inhibition of adventitial p67^phox activity would attenuate angioplasty-induced hyperplasia. To test this hypothesis, we treated the adventitia of carotid arteries with a control adenovirus (Ad-control), a virus expressing dominant-negative p67^phox (Ad-p67dn), or a virus expressing a competitive peptide (gp91ds) targeting the p47^phox-gp91^phox interaction (Ad-gp91ds). Common carotid arteries (CCAs) from male Sprague-Dawley rats were transfected with Ad-control, Ad-p67dn, or Ad-gp91ds in pluronic gel. After 2 days, a 2-F (Fogarty) catheter was used to injure CCAs in vivo. After 14 days, CCAs were perfusion-fixed and analyzed. In 13 experiments, digital morphometry suggested a reduction of neointimal hyperplasia with Ad-p67dn compared with Ad-control; however, the reduction did not reach statistical significance (P = 0.058). In contrast, a significant reduction was achieved with Ad-gp91ds (P = 0.006). No changes in medial area or remodeling were observed with either treatment. Moreover, adventitial fibroblast proliferation in vitro was inhibited by Ad-gp91ds but not by Ad-p67dn, despite confirmation that Ad-p67dn inhibits NADPH oxidase in fibroblasts. These data appear to suggest that a multicomponent vascular NADPH oxidase plays a role in neointimal hyperplasia. However, inhibition of p47^phox may be more effective than inhibition of p67^phox at attenuating neointimal growth.

NADPH oxidase; p47^phox; adventitia; restenosis

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