Adenovirus-mediated delivery of the Gax transcription factor to rat carotid arteries inhibits smooth muscle proliferation and induces apoptosis

Adenovirus-mediated gene delivery in animal models of vascular injury has p rovided insights into the mechanisms underlying vessel wall pathologies. We have previously demonstrated that overexpression of the Gax transcription factor inhibits neointimal formation in rat and rabbit models of arterial i njury. Here, we evaluate potential mechanisms for the reduction in stenotic lesion size due to Gax over-expression. At 3, 7 and 14 days after injury t he Ad-GaX-infected arteries displayed a marked decrease in medial vascular smooth muscle cell number (3 days, 54% reduction P < 0.01; 7 days, 41% redu ction P < 0.003; 14 days, 49% reduction P < 0.02). At 3 days after injury, PCNA expression was attenuated in the Ad-Gax-treated vessels compared with control vessels (65% reduction P < 0.02), indicating a reduction in cellula r proliferation. At 7 days and 14 days after injury Ad-Gax-infected arterie s exhibited elevated number of TUNEL-positive medial VSMCs compared with co ntrol-treated arteries (7 days, 9.2-fold increase P < 0.03; 14 days, 17.2-f old increase P < 0.03), indicating an induction of apoptotic cell death. Th ese data suggest that deregulated Gax expression induces first cell cycle a rrest and then apoptosis in the vascular smooth muscle cells that contribut e to the neointimal layer. Therefore, the efficacy of this therapeutic stra tegy appears to result from the ability of the Gax transcriptional regulato r to modulate multiple cellular responses.