Nuclear Smooth Muscle α-actin Participates in Vascular Smooth Muscle Cell Differentiation

Authors

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

Publication Date

10-1-2023

Journal

Nature Cardiovascular Research

Abstract

Missense variants throughout ACTA2, encoding smooth muscle α-actin (αSMA), 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 αSMA 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 αSMA variant shows decreased nuclear localization. Primary SMCs from Acta2SMC-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 αSMA participates in SMC differentiation, and loss of this nuclear activity occurs with ACTA2 p.R179 pathogenic variants.

Comments

Supplementary Materials

PMID: 38919852