title: Mechanisms involved in extracellular matrix remodeling and arterial stiffness induced by hyaluronan accumulation.
abstract: OBJECTIVE
  Hyperglycemia induces hyaluronan (HA) accumulation in the vasculature. Excessive accumulation of HA around the vascular smooth muscle cells (VSMC) results in increased aortic stiffness and strength and accelerated atherosclerosis in ApoE(-)/(-) mice. We hypothesized that HA accumulation primes the vasculature for atherosclerosis by crosslinking and reorganizing the extracellular matrix (ECM) and by pushing VSMC differentiation towards a less mature phenotype.
  
  
  METHODS
  Aortas from HAS-2 transgenic (Tg) mice and wild type mice were used for all experiments. Biomechanics and cross-sectional area measurements were performed before and after HA digestion. The vessel and ECM composition was examined by immunoblotting and electron microscopy. Primary VSMC cultures were examined by qPCR and thymidine incorporation.
  
  
  RESULTS
  Tg mice aorta cross-sectional area was increased before (14%, p = 0.0148), but not after HA digestion (p = 0.3437). The increase in vessel stiffness (32%, p = 0.0217) and strength (31%, p = 0.0043) in the Tg aorta persisted after HA digestion. Crosslinking of HA by heavy chains from Inter-α-Inhibitor was increased (175%, p = 0.0006). The Tg VSMCs have the appearance of a synthetic phenotype supported by a 40% decrease in α-smooth muscle actin isoform X1 (p = 0.0296) and an increase in proliferation (63%, p = 0.0048) and osteoprotegerin production (133%, p = 0.0010) in cultured Tg VSMCs.
  
  
  CONCLUSIONS
  Our results show that induced HA accumulation is followed by increased HA crosslinking and create a shift in VSMC phenotype and proliferation. These findings may provide a mechanism for how hyperglycemia through HA accumulation prime the vascular wall for cholesterol and leucocyte accumulation and development of atherosclerosis.
authors.affiliation: The Research Laboratory for Biochemical Pathology, The Institute of Clinical Medicine, Aarhus University, Aarhus University Hospital, Noerrebrogade 44, Bld. 3B -1, DK-8000 Aarhus C, Denmark. Electronic address: Karen.Lorentzen@clin.au.dk.
authors.forename: Karen Axelgaard
authors.initials: KA
authors.lastname: Lorentzen
authors.affiliation: The Research Laboratory for Biochemical Pathology, The Institute of Clinical Medicine, Aarhus University, Aarhus University Hospital, Noerrebrogade 44, Bld. 3B -1, DK-8000 Aarhus C, Denmark. Electronic address: Chai_song@hotmail.com.
authors.forename: Song
authors.initials: S
authors.lastname: Chai
authors.affiliation: The Research Laboratory for Biochemical Pathology, The Institute of Clinical Medicine, Aarhus University, Aarhus University Hospital, Noerrebrogade 44, Bld. 3B -1, DK-8000 Aarhus C, Denmark. Electronic address: Chenhuilu67@aliyun.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Institute of Biomedicine, Aarhus University, Wilhelm Meyers Allé 3, Bld. 1233, Room 132, 8000 Aarhus C, Denmark. Electronic address: Ccd@biomed.au.dk.
authors.forename: Carl Christian
authors.initials: CC
authors.lastname: Danielsen
authors.affiliation: Pharmacology, Institute of Biomedicine, Research and Education, East. Aarhus University Bartholins Allé 6, Bld. 1242, Room 341, 8000 Aarhus C, Denmark. Electronic address: us@biomed.au.dk.
authors.forename: Ulf
authors.initials: U
authors.lastname: Simonsen
authors.affiliation: The Research Laboratory for Biochemical Pathology, The Institute of Clinical Medicine, Aarhus University, Aarhus University Hospital, Noerrebrogade 44, Bld. 3B -1, DK-8000 Aarhus C, Denmark. Electronic address: lwb@ki.au.dk.
authors.forename: Lise
authors.initials: L
authors.lastname: Wogensen
mesh_terms: D000276:Adjuvants, Immunologic / Q000493:pharmacokinetics; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015153:Blotting, Western; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006820:Hyaluronic Acid / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D066253:Vascular Remodeling / Q000187:drug effects* / Q000235:genetics; D059289:Vascular Stiffness / Q000187:drug effects / Q000502:physiology*
chemical_list: D000276:Adjuvants, Immunologic; C094556:Ecm1 protein, mouse; D016326:Extracellular Matrix Proteins; D012313:RNA; D006820:Hyaluronic Acid
keywords: Arterial stiffness; Atherosclerosis; Diabetic angiopathy; Extracellular matrix; Hyaluronan; Inter-α-Inhibitor; Vascular smooth muscle cells