title: Deletion of Hyaluronan Synthase 3 Inhibits Neointimal Hyperplasia in Mice.
abstract: OBJECTIVE
  Hyaluronan (HA) is a polymeric glucosaminoglycan that forms a provisional extracellular matrix in diseased vessels. HA is synthesized by 3 different HA synthases (HAS1, HAS2, and HAS3). Aim of this study was to unravel the role of the HAS3 isoenzyme during experimental neointimal hyperplasia.
  
  
  RESULTS
  Neointimal hyperplasia was induced in Has3-deficient mice by ligation of the carotid artery. HA in the media of Has3-deficient mice was decreased 28 days after ligation, and neointimal hyperplasia was strongly inhibited. However, medial and luminal areas were unaffected. Cell density, proliferation, and apoptosis were not altered, suggesting a proportional decrease of both, the number of cells and extracellular matrix. In addition, endothelial function as determined by acetylcholine-induced relaxation of aortic rings, immunoblotting of endothelial nitric oxide synthase, and arterial blood pressure were not affected. Furthermore, the oxidative stress response was not affected as determined in total protein extracts from aortae. Transcriptome analysis comparing control versus ligated carotid arteries hinted toward a mitigated differential regulation of various signaling pathways in Has3-deficient mice in response to ligation that were related to vascular smooth muscle cell (VSMC) migration, including focal adhesions, integrins, mitogen-activated protein kinase, and phosphatidylinositol signaling system. Lentiviral overexpression of HAS3 in VSMC supported the migratory phenotype of VSMC in response to platelet-derived growth factor BB in vitro. Accordingly, knockdown of HAS3 reduced the migratory response to platelet-derived growth factor BB and in addition decreased the expression of PDGF-B mRNA.
  
  
  CONCLUSIONS
  HAS3-mediated HA synthesis after vessel injury supports seminal signaling pathways in activation of VSMC, increases platelet-derived growth factor BB-mediated migration, and in turn enhances neointimal hyperplasia in vivo.
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.|Cardiovascular Research Institute Düsseldorf (CARID), Universitätsklinikum der Heinrich-Heine Universität, Düsseldorf, Germany.
authors.forename: Lena S
authors.initials: LS
authors.lastname: Kiene
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.|Cardiovascular Research Institute Düsseldorf (CARID), Universitätsklinikum der Heinrich-Heine Universität, Düsseldorf, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Homann
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Tatsiana
authors.initials: T
authors.lastname: Suvorava
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.|Cardiovascular Research Institute Düsseldorf (CARID), Universitätsklinikum der Heinrich-Heine Universität, Düsseldorf, Germany.
authors.forename: Berit
authors.initials: B
authors.lastname: Rabausch
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.|Cardiovascular Research Institute Düsseldorf (CARID), Universitätsklinikum der Heinrich-Heine Universität, Düsseldorf, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Müller
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Kojda
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.|Cardiovascular Research Institute Düsseldorf (CARID), Universitätsklinikum der Heinrich-Heine Universität, Düsseldorf, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Kretschmer
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.|Cardiovascular Research Institute Düsseldorf (CARID), Universitätsklinikum der Heinrich-Heine Universität, Düsseldorf, Germany.
authors.forename: Sören
authors.initials: S
authors.lastname: Twarock
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.|Cardiovascular Research Institute Düsseldorf (CARID), Universitätsklinikum der Heinrich-Heine Universität, Düsseldorf, Germany.
authors.forename: Guang
authors.initials: G
authors.lastname: Dai
authors.affiliation: Biologisch-Medizinisches Forschungszentrum (BMFZ), Universitätsklinikum der Heinrich-Heine- Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Deenen
authors.affiliation: Deutsches Diabetes Zentrum, Düsseldorf, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hartwig
authors.affiliation: Deutsches Diabetes Zentrum, Düsseldorf, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lehr
authors.affiliation: Biologisch-Medizinisches Forschungszentrum (BMFZ), Universitätsklinikum der Heinrich-Heine- Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Köhrer
authors.affiliation: Divisions of Pulmonary & Vascular Biology and Neonatal-Perinatal Medicine, Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Rashmin C
authors.initials: RC
authors.lastname: Savani
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.|Cardiovascular Research Institute Düsseldorf (CARID), Universitätsklinikum der Heinrich-Heine Universität, Düsseldorf, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Grandoch
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.|Cardiovascular Research Institute Düsseldorf (CARID), Universitätsklinikum der Heinrich-Heine Universität, Düsseldorf, Germany.
authors.forename: Jens W
authors.initials: JW
authors.lastname: Fischer
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002340:Carotid Artery Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017536:Carotid Artery, Common / Q000201:enzymology / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005838:Genotype; D014453:Glucuronosyltransferase / Q000172:deficiency* / Q000235:genetics; D000076002:Hyaluronan Synthases; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D058426:Neointima; D010641:Phenotype; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D014453:Glucuronosyltransferase; C491356:Has3 protein, mouse; D000076002:Hyaluronan Synthases
keywords: carotid arteries; extracellular matrix; hyaluronan; neointima; smooth muscle cells