402 Circulation Research July 22, 2016 (2) editing generated mutations in binding sites for splicing factors (SRp55), and (3) editing shortened CA repeat regions that might also influence splicing. The relative contributions of these potential mechanisms remain to be determined. ADAR1 upregulation and RNA editing was observed in both rat and human SMC and in multiple introns of 2 different contractile genes, MYH11 and ACTA2. Importantly, this phenomenon was also observed in response to vascular injury in 2 different in vivo models. ADAR1 expression was induced and the pre-mRNAs for Myh11 and Acta2 were accumulated in rat carotid artery after balloon angioplasty, and the kinetics of this response were consistent with a role for RNA editing in mediating the contractile protein repression post injury. ADAR1 homozygous knockout is lethal, 7 but heterozygous deletion dramatically reduced neointimal hyperplasia in a mouse wire injury model, revealing a causal role for ADAR1 in phenotypic modulation in vivo. ADAR1 knockdown similarly promoted a contractile phenotype in cultured SMC. Although SMC express both ADAR1 and ADAR2, only ADAR1 was regulated by PDGF, and ADAR2 did not seem to compensate for ADAR1 loss of function. Additional evidence implicated the editing and splicing mechanism, as an editing-deficient ADAR1 mutant or the general splicing inhibitor isoginkgetin was unable to modulate contractile mRNA levels in SMC. Deciphering the signaling mechanisms by which ADAR1 is regulated by PDGF will be of interest, as will the question of whether there is a consensus motif that targets particular adenine for editing by ADAR1 in SMC mRNAs.