Smooth muscle hyperplasia due to loss of smooth muscle -actin is driven by activation of focal adhesion kinase, altered p53 localization and increased levels of platelet-derived growth factor receptor-. Academic Article uri icon


  • Mutations in ACTA2, encoding the smooth muscle cell (SMC)-specific isoform of -actin (-SMA), cause thoracic aortic aneurysms and dissections and occlusive vascular diseases, including early onset coronary artery disease and stroke. We have shown that occlusive arterial lesions in patients with heterozygous ACTA2 missense mutations show increased numbers of medial or neointimal SMCs. The contribution of SMC hyperplasia to these vascular diseases and the pathways responsible for linking disruption of -SMA filaments to hyperplasia are unknown. Here, we show that the loss of Acta2 in mice recapitulates the SMC hyperplasia observed in ACTA2 mutant SMCs and determine the cellular pathways responsible for SMC hyperplasia. Acta2(-/-) mice showed increased neointimal formation following vascular injury in vivo, and SMCs explanted from these mice demonstrated increased proliferation and migration. Loss of -SMA induced hyperplasia through focal adhesion (FA) rearrangement, FA kinase activation, re-localization of p53 from the nucleus to the cytoplasm and increased expression and ligand-independent activation of platelet-derived growth factor receptor beta (Pdgfr-). Disruption of -SMA in wild-type SMCs also induced similar cellular changes. Imatinib mesylate inhibited Pdgfr- activation and Acta2(-/-) SMC proliferation in vitro and neointimal formation with vascular injury in vivo. Loss of -SMA leads to SMC hyperplasia in vivo and in vitro through a mechanism involving FAK, p53 and Pdgfr-, supporting the hypothesis that SMC hyperplasia contributes to occlusive lesions in patients with ACTA2 missense mutations.

published proceedings

  • Hum Mol Genet

altmetric score

  • 0.75

author list (cited authors)

  • Papke, C. L., Cao, J., Kwartler, C. S., Villamizar, C., Byanova, K. L., Lim, S., ... Milewicz, D. M.

citation count

  • 34

complete list of authors

  • Papke, Christina L||Cao, Jiumei||Kwartler, Callie S||Villamizar, Carlos||Byanova, Katerina L||Lim, Soon-Mi||Sreenivasappa, Harini||Fischer, Grant||Pham, John||Rees, Meredith||Wang, Miranda||Chaponnier, Christine||Gabbiani, Giulio||Khakoo, Aarif Y||Chandra, Joya||Trache, Andreea||Zimmer, Warren||Milewicz, Dianna M

publication date

  • August 2013