Reversal of GATA-6 downregulation promotes smooth muscle differentiation and inhibits intimal hyperplasia in balloon-injured rat carotid artery

The GATA-6 transcription factor is expressed in quiescent vascular smooth m uscle cells (VSMCs) in culture, and levels of its transcript are rapidly do wnregulated on mitogen stimulation. In this study, we demonstrate that the GATA-6 transcript, protein, and DNA-binding activity are downregulated in r at carotid arteries on balloon injury. Downregulation was detected at 1 and 3 days after injury and recovered by 7 days. To assess the role of GATA-6 downregulation in injury-induced vascular lesion formation, adenoviral vect ors were used to express wild-type human GATA-6 cDNA (Ad-GATA6) or an inact ive mutant cDNA that lacks a portion of the zinc-finger domain (Ad-GATA6 De lta ZF). Adenovirus-mediated GATA-6 gene transfer to the vessel wall after balloon injury partially restored the levels of GATA-6 protein and DNA-bind ing activity to before injury levels, The local delivery of Ad-GATA6 but no t Ad-GATA6 Delta ZF inhibited lesion formation by 46% relative to saline co ntrol and 50% relative to a control adenovirus that expressed lacZ. Local d elivery of Ad-GATA6 also reversed changes in the expression patterns of smo oth muscle myosin heavy chain, smooth muscle alpha-actin, calponin, vinculi n, metavinculin, and proliferating cell nuclear antigen that are associated with injury-induced VSMC phenotypic modulation. These data indicate that t he injury-induced downregulation of GATA-6 is an essential feature of VSMC phenotypic modulation that contributes to vessel lesion formation.