Crucial role of hyaluronan in neointimal formation after vascular injury

• Published in: PloS one 2013-03, Vol.8 (3), p.e58760
• Main Authors: Kashima, Yuichiro, Takahashi, Masafumi, Shiba, Yuji, Itano, Naoki, Izawa, Atsushi, Koyama, Jun, Nakayama, Jun, Taniguchi, Shun'ichiro, Kimata, Koji, Ikeda, Uichi
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Arteries; Arteriosclerosis; Atherosclerosis; Atherosclerosis - complications; Biology; Blotting, Western; Bone marrow; Bromodeoxyuridine; Cardiovascular diseases; CD44 antigen; Cell Movement - drug effects; Cell Proliferation - drug effects; Cytokines; Cytokines - metabolism; DNA Primers - genetics; Extracellular matrix; Genetic engineering; HAS2 gene; Humans; Hyaluronic acid; Hyaluronic Acid - antagonists & inhibitors; Hyaluronic Acid - metabolism; Hymecromone - analogs & derivatives; Hymecromone - pharmacology; Immunohistochemistry; Inflammation; Injuries; Lesions; Liquid oxygen; Medical research; Medicine; Mice; Mice, Transgenic; Microscopy, Confocal; Migratory species; Muscle, Smooth, Vascular - metabolism; Muscles; Neointima - etiology; Neointima - metabolism; Oxygen; Pathogenesis; Physiology; Reactive oxygen species; Reactive Oxygen Species - metabolism; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RhoA protein; Rodents; Smooth muscle; University graduates; Vascular System Injuries - complications
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0058760

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. 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. VSMC-derived HA promotes neointimal formation after vascular injury, and HA may be a potential therapeutic target for cardiovascular disease.