Journal article
Smooth muscle hyperplasia due to loss of smooth muscle α-actin is driven by activation of focal adhesion kinase, altered p53 localization and increased levels of platelet-derived growth factor receptor-β
Human molecular genetics, v 22(15), pp 3123-3137
01 Aug 2013
PMID: 23591991
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Mutations in ACTA2, encoding the smooth muscle cell (SMC)-specific isoform of alpha-actin (alpha-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 alpha-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 alpha-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-beta). Disruption of alpha-SMA in wildtype SMCs also induced similar cellular changes. Imatinib mesylate inhibited Pdgfr-beta activation and Acta2(-/-) SMC proliferation in vitro and neointimal formation with vascular injury in vivo. Loss of alpha-SMA leads to SMC hyperplasia in vivo and in vitro through a mechanism involving FAK, p53 and Pdgfr-beta, supporting the hypothesis that SMC hyperplasia contributes to occlusive lesions in patients with ACTA2 missense mutations.
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Details
- Title
- Smooth muscle hyperplasia due to loss of smooth muscle α-actin is driven by activation of focal adhesion kinase, altered p53 localization and increased levels of platelet-derived growth factor receptor-β
- Creators
- Christina L. Papke - The University of Texas Health Science Center at HoustonJiumei Cao - The University of Texas Health Science Center at HoustonCallie S. Kwartler - The University of Texas Health Science Center at HoustonCarlos Villamizar - The University of Texas Health Science Center at HoustonKaterina L. Byanova - The University of Texas Health Science Center at HoustonSoon-Mi Lim - Texas A&M Health Science CenterHarini Sreenivasappa - Texas A&M Health Science CenterGrant Fischer - The University of Texas Health Science Center at HoustonJohn Pham - The University of Texas Health Science Center at HoustonMeredith Rees - The University of Texas Health Science Center at HoustonMiranda Wang - The University of Texas Health Science Center at HoustonChristine Chaponnier - University of GenevaGiulio Gabbiani - University of GenevaAarif Y. Khakoo - AmgenJoya Chandra - The University of Texas MD Anderson Cancer CenterAndreea Trache - Texas A&M UniversityWarren Zimmer - Texas A&M Health Science CenterDianna M. Milewicz - The University of Texas Health Science Center at Houston
- Publication Details
- Human molecular genetics, v 22(15), pp 3123-3137
- Publisher
- Oxford Univ Press
- Number of pages
- 15
- Grant note
- Whitaker Foundation Richard T. Pisani Funds 0747334 / NSF; National Science Foundation (NSF) 310030_125320 / Swiss National Science Foundation; Swiss National Science Foundation (SNSF) 0747334 / Direct For Mathematical & Physical Scien; Division Of Physics; National Science Foundation (NSF); NSF - Directorate for Mathematical & Physical Sciences (MPS) 310030_125320 / Swiss National Science Foundation (SNF); Swiss National Science Foundation (SNSF) P50HL083794-01; R01 HL62594; P01 HL110869 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Alpha Omega Alpha Carolyn L. Kuckein Student Research Fellowship UL1 RR024148 / National Institutes of Health from the National Center for Research Resources; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) Center for Clinical and Translational Sciences
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Cell Imaging Center
- Web of Science ID
- WOS:000321452600013
- Scopus ID
- 2-s2.0-84880265166
- Other Identifier
- 991022008194104721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Genetics & Heredity