title: Crucial role of hyaluronan in neointimal formation after vascular injury.
abstract: BACKGROUND
  Hyaluronan (HA) is a primary component of the extracellular matrix of cells, and it is involved in the pathogenesis of atherosclerosis. The purpose of this study was to investigate the role of HA in neointimal formation after vascular injury and determine its tissue-specific role in vascular smooth muscle cells (VSMCs) by using a cre-lox conditional transgenic (cTg) strategy.
  
  
  RESULTS
  HA was found to be expressed in neointimal lesions in humans with atherosclerosis and after wire-mediated vascular injury in mice. Inhibition of HA synthesis using 4-methylumbelliferone markedly inhibited neointimal formation after injury. In vitro experiments revealed that low-molecular-weight HA (LMW-HA) induced VSMC activation, including migration, proliferation, and production of inflammatory cytokines, and reactive oxygen species (ROS). The migration and proliferation of VSMCs were mediated by the CD44/RhoA and CD44/ERK1/2 pathways, respectively. Because HA synthase 2 (HAS2) is predominantly expressed in injured arteries, we generated cTg mice that overexpress the murine HAS2 gene specifically in VSMCs (cHAS2/CreSM22α mice) and showed that HA overexpression markedly enhanced neointimal formation after cuff-mediated vascular injury. Further, HA-overexpressing VSMCs isolated from cHAS2/CreSM22α mice showed augmented migration, proliferation, and production of inflammatory cytokines and ROS.
  
  
  CONCLUSIONS
  VSMC-derived HA promotes neointimal formation after vascular injury, and HA may be a potential therapeutic target for cardiovascular disease.
authors.affiliation: Department of Cardiovascular Medicine, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Kashima
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shiba
authors.forename: Naoki
authors.initials: N
authors.lastname: Itano
authors.forename: Atsushi
authors.initials: A
authors.lastname: Izawa
authors.forename: Jun
authors.initials: J
authors.lastname: Koyama
authors.forename: Jun
authors.initials: J
authors.lastname: Nakayama
authors.forename: Shun'ichiro
authors.initials: S
authors.lastname: Taniguchi
authors.forename: Koji
authors.initials: K
authors.lastname: Kimata
authors.forename: Uichi
authors.initials: U
authors.lastname: Ikeda
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D050197:Atherosclerosis / Q000150:complications*; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006923:Hymecromone / Q000031:analogs & derivatives / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D058426:Neointima / Q000209:etiology* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D057772:Vascular System Injuries / Q000150:complications*
chemical_list: D016207:Cytokines; D017931:DNA Primers; D017382:Reactive Oxygen Species; D006923:Hymecromone; D006820:Hyaluronic Acid; D001973:Bromodeoxyuridine