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

Callie S. Kwartler; Albert J. Pedroza; Anita Kaw; Pujun Guan; Shuangtao Ma; Xue yan Duan; Caroline Kernell; Charis Wang; Jose Emiliano Esparza Pinelo; Mikayla S. Borthwick Bowen; Jiyuan Chen; Yuan Zhong; Sanjay Sinha; Xuetong Shen; Michael P. Fischbein; Dianna M. Milewicz

doi:10.1038/s44161-023-00337-4

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

Callie S. Kwartler, Albert J. Pedroza, Anita Kaw, Pujun Guan, Shuangtao Ma, Xue yan Duan, Caroline Kernell, Charis Wang, Jose Emiliano Esparza Pinelo, Mikayla S. Borthwick Bowen, Jiyuan Chen, Yuan Zhong, Sanjay Sinha, Xuetong Shen, Michael P. Fischbein, Dianna M. Milewicz

Epigenetics & Molecular Carcinogenesis

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	937-955
Number of pages	19
Journal	Nature Cardiovascular Research
Volume	2
Issue number	10
DOIs	https://doi.org/10.1038/s44161-023-00337-4
State	Published - Oct 2023

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology (miscellaneous)
Cell Biology
Medicine (miscellaneous)
Cardiology and Cardiovascular Medicine

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10.1038/s44161-023-00337-4

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Kwartler, C. S., Pedroza, A. J., Kaw, A., Guan, P., Ma, S., Duan, X. Y., Kernell, C., Wang, C., Esparza Pinelo, J. E., Borthwick Bowen, M. S., Chen, J., Zhong, Y., Sinha, S., Shen, X., Fischbein, M. P., & Milewicz, D. M. (2023). Nuclear smooth muscle α-actin participates in vascular smooth muscle cell differentiation. Nature Cardiovascular Research, 2(10), 937-955. https://doi.org/10.1038/s44161-023-00337-4

Kwartler, CS, Pedroza, AJ, Kaw, A, Guan, P, Ma, S, Duan, XY, Kernell, C, Wang, C, Esparza Pinelo, JE, Borthwick Bowen, MS, Chen, J, Zhong, Y, Sinha, S, Shen, X, Fischbein, MP & Milewicz, DM 2023, 'Nuclear smooth muscle α-actin participates in vascular smooth muscle cell differentiation', Nature Cardiovascular Research, vol. 2, no. 10, pp. 937-955. https://doi.org/10.1038/s44161-023-00337-4

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title = "Nuclear smooth muscle α-actin participates in vascular smooth muscle cell differentiation",

abstract = "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{\textquoteright}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.",

author = "Kwartler, {Callie S.} and Pedroza, {Albert J.} and Anita Kaw and Pujun Guan and Shuangtao Ma and Duan, {Xue yan} and Caroline Kernell and Charis Wang and {Esparza Pinelo}, {Jose Emiliano} and {Borthwick Bowen}, {Mikayla S.} and Jiyuan Chen and Yuan Zhong and Sanjay Sinha and Xuetong Shen and Fischbein, {Michael P.} and Milewicz, {Dianna M.}",

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doi = "10.1038/s44161-023-00337-4",

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AU - Pedroza, Albert J.

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AU - Guan, Pujun

AU - Ma, Shuangtao

AU - Duan, Xue yan

AU - Kernell, Caroline

AU - Wang, Charis

AU - Esparza Pinelo, Jose Emiliano

AU - Borthwick Bowen, Mikayla S.

AU - Chen, Jiyuan

AU - Zhong, Yuan

AU - Sinha, Sanjay

AU - Shen, Xuetong

AU - Fischbein, Michael P.

AU - Milewicz, Dianna M.

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N2 - 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.

AB - 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.

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

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