title: Inhibition of hyaluronan synthesis accelerates murine atherosclerosis: novel insights into the role of hyaluronan synthesis.
abstract: BACKGROUND
  Hyaluronan is thought to mediate neointimal hyperplasia but also vasoprotection as an integral component of the endothelial glycocalyx. The present study addressed for the first time the effects of long-term pharmacological inhibition of hyaluronan synthesis on vascular function and atherosclerosis.
  
  
  RESULTS
  Four-week-old apolipoprotein E-deficient mice on a Western diet received orally an inhibitor of hyaluronan synthesis, 4-methylumbelliferone (4-MU; 10 mg/g body wt), resulting in 600 nmol/L 4-MU in plasma. As a result, aortic plaque burden was markedly increased at 25 weeks. Furthermore, acetylcholine-dependent relaxation of aortic rings was decreased and mean arterial blood pressure was increased in response to 4-MU. However, hydralazine blunted the hypertensive effect of 4-MU without inhibiting the proatherosclerotic effect. A photothrombosis model revealed a prothrombotic state that was not due to increased platelet activation or increased thrombin activation as monitored by CD62P expression and the endogenous thrombin potential. Importantly, increased recruitment of macrophages to vascular lesions was detected after 2 and 21 weeks of 4-MU treatment by immunohistochemistry, by intravital microscopy, and in a peritonitis model. As a potential underlying mechanism, severe damage of the endothelial glycocalyx after 2 and 21 weeks of treatment with 4-MU was detected by electron microscopy of the innominate artery and myocardial capillaries. Furthermore, 600 nmol/L 4-MU inhibited hyaluronan synthesis in cultured endothelial cells.
  
  
  CONCLUSIONS
  The data suggest that systemic inhibition of hyaluronan synthesis by 4-MU interferes with the protective function of the endothelial glycocalyx, thereby facilitating leukocyte adhesion, subsequent inflammation, and progression of atherosclerosis.
authors.affiliation: Institut für Pharmakologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Nagy
authors.forename: Till
authors.initials: T
authors.lastname: Freudenberger
authors.forename: Ariane
authors.initials: A
authors.lastname: Melchior-Becker
authors.forename: Katharina
authors.initials: K
authors.lastname: Röck
authors.forename: Michael
authors.initials: M
authors.lastname: Ter Braak
authors.forename: Holger
authors.initials: H
authors.lastname: Jastrow
authors.forename: Martina
authors.initials: M
authors.lastname: Kinzig
authors.forename: Susann
authors.initials: S
authors.lastname: Lucke
authors.forename: Tatsiana
authors.initials: T
authors.lastname: Suvorava
authors.forename: Georg
authors.initials: G
authors.lastname: Kojda
authors.forename: Artur A
authors.initials: AA
authors.lastname: Weber
authors.forename: Fritz
authors.initials: F
authors.lastname: Sörgel
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
authors.forename: Süleyman
authors.initials: S
authors.lastname: Ergün
authors.forename: Jens W
authors.initials: JW
authors.lastname: Fischer
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D019276:Glycocalyx / Q000187:drug effects / Q000378:metabolism; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006923:Hymecromone / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D014665:Vasodilator Agents; D006923:Hymecromone; D006820:Hyaluronic Acid; D000109:Acetylcholine