Objective: We and others have shown that smooth muscle (SMC) marker gene down-regulation is an early event in vascular disease and involves the transcription factor KLF4. However, the molecular mechanisms mediating continued repression following KLF4 release remain unknown. Recently, we have shown that ZFP148 is critical in SMCs during aortic aneurysm formation; however, no studies have investigated the molecular mechanisms of this process. The study objective was to determine what factors mediate SMC down-regulation after KLF4 binding is diminished. Methods and Results: 8-12 week male mice (n=8 per group) underwent carotid ligation and were harvested at day 7 for chromatin immunoprecipitation analysis (ChIP) for KLF4, KLF2, ZFP148, NF-1, Sp1, Sp3 and YY1. ZFP148, NF-1 and KLF2 were significantly elevated following ligation injury. In separate experiments, 8-12 week male (n=10/group) C57/B6 mice underwent carotid ligation and were harvested at 1, 3, 7, and 14, days for ChIP analysis for ZFP148 and NF-1. ZFP148 and NF-1 bound SMC marker genes SM-actin, SM22α and SM-MHC 7 and 14 days following injury. Since ZFP148 and NF-1 bound and could mediate SMC marker gene repression and ZFP148 has no current known role in SMC down-regulation, 8-12 week male (n=14/group) ZFP flx/flx Myh11 Cre+(SMC specific ZFP148 KO), Myh11 ZFP148 flx/wt Cre+(Heterozygous ZFP148 KO) and Myh11 ZFP wt/wt Cre+ (WT) underwent carotid ligation following tamoxifen administration. Neointimal area was significantly increased 21 days following injury in ZFP148 SMC KO mice. In separate experiments, ZFP148 flx/flx ERT Cre+ (ZFP148 KO, n=12/group) and ZFP148 flx/flx ERT Cre-(WT) mice also underwent carotid ligation following tamoxifen treatment. Neointimal area was also significantly increased in ZFP148 KO mice. ChIP assays were performed in vitro and in vivo using NF-1 KO cells. ZFP148 bound via ChIP analysis to SMC marker genes in vitro and in vivo; however, ZFP148 binding declined significantly in NF-1 KO SMCs versus WT SMCs. Conclusions: ZFP148 activity is critical for vascular disease and helps modulate smooth muscle phenotypic modulation during vascular injury in coordination with NF-1. As such, ZFP148 is another zinc finger protein with potential therapeutic relevance.