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Nuclear Smooth Muscle a-actin Participates in Vascular Smooth Muscle Cell Differentiation.
Nuclear Smooth Muscle a-actin Participates in Vascular Smooth Muscle Cell Differentiation. Nature cardiovascular research Kwartler, C. S., Pedroza, A. J., Kaw, A., Guan, P., Ma, S., Duan, X. Y., Kernell, C., Wang, C., Pinelo, J. E., Bowen, M. S., Chen, J., Zhong, Y., Sinha, S., Shen, X., Fischbein, M. P., Milewicz, D. M. 2023; 2 (10): 937-955Abstract
Missense variants throughout ACTA2, encoding smooth muscle a-actin (aSMA), predispose to adult-onset thoracic aortic disease, but variants disrupting arginine 179 (R179) lead to Smooth Muscle Dysfunction Syndrome (SMDS) characterized by diverse childhood-onset vascular diseases. Here we show that aSMA localizes to the nucleus in wildtype (WT) smooth muscle cells (SMCs), enriches in the nucleus with SMC differentiation, and associates with chromatin remodeling complexes and SMC contractile gene promotors. The ACTA2 p.R179 aSMA variant shows decreased nuclear localization. Primary SMCs from Acta2 SMC-R179C/+ mice are less differentiated than WT SMCs in vitro and in vivo and have global changes in chromatin accessibility. Induced pluripotent stem cells from patients with ACTA2 p.R179 variants fail to fully differentiate from neuroectodermal progenitor cells to SMCs, and single-cell transcriptomic analyses of an ACTA2 p.R179H patient's aortic tissue show increased SMC plasticity. Thus, nuclear aSMA participates in SMC differentiation, and loss of this nuclear activity occurs with ACTA2 p.R179 pathogenic variants.
View details for DOI 10.1038/s44161-023-00337-4
View details for PubMedID 38919852
View details for PubMedCentralID PMC11198982