Nuclear smooth muscle α-actin participates in vascular smooth muscle cell differentiation

Missense variants throughout ACTA2 , encoding α-smooth muscle actin (αSMA), predispose to adult-onset thoracic aortic disease, but variants disrupting arginine 179 (R179) lead to smooth muscle dysfunction syndrome characterized by diverse childhood-onset vascular diseases. Here we show that αSMA localizes to the nucleus in wild-type smooth muscle cells (SMCs), enriches in the nucleus with SMC differentiation, and associates with chromatin remodeling complexes and SMC contractile gene promoters. The ACTA2 p.Arg179 αSMA variant shows decreased nuclear localization. Primary SMCs from Acta2 SMC-R179C/+ mice are less differentiated than wild-type SMCs in vitro and in vivo and have global changes in chromatin accessibility. Induced pluripotent stem cells from participants with ACTA2 p.Arg179 variants fail to fully differentiate from neuroectodermal progenitor cells to SMCs, and single-cell transcriptomic analyses of an ACTA2 p.Arg179His participant’s aortic tissue show increased SMC plasticity. Thus, nuclear αSMA participates in SMC differentiation, and loss of this nuclear activity occurs with ACTA2 p.Arg179 pathogenic variants.