title: Differential effects of medroxyprogesterone acetate on thrombosis and atherosclerosis in mice.
abstract: OBJECTIVE
  The risk for cardiovascular events including venous and arterial disease and stroke is elevated after treatment with estrogen and medroxyprogesterone acetate (MPA) in postmenopausal women. Here, we have investigated the effect of MPA on arterial thrombosis and atherosclerosis in a murine model of atherosclerosis.
  
  
  METHODS
  Apolipoprotein E (ApoE)-/- mice were bilaterally ovariectomized and treated with placebo, MPA (27.7 microg day(-1)) and MPA + 17-beta-oestradiol (E2; 1.1 microg day(-1)) for 90 days, on a Western-type diet. Thrombotic response was measured in a photothrombosis model, platelet activation by fluorescence activated cell sorting (FACS) analysis (CD62P) and thrombin generation by the endogenous thrombin potential (ETP). Furthermore, aortic plaque burden and aortic root plaque composition were determined.
  
  
  RESULTS
  MPA and MPA + E2-treated animals showed an aggravated thrombotic response shown by significantly reduced time to stable occlusion. The pro-thrombotic effect of MPA was paralleled by increased ETP whereas platelet activation was not affected. Furthermore, MPA + E2 reduced the number of cells positive for alpha-smooth muscle actin and increased hyaluronan in the plaque matrix. Interestingly, total plaque burden was reduced by MPA but unchanged by MPA + E2.
  
  
  CONCLUSIONS
  Long-term treatment with MPA and MPA + E2 increased arterial thrombosis despite inhibitory effects of MPA on atherosclerosis in ApoE-deficient mice. Increased thrombin formation, reduced smooth muscle content and remodelling of non-collagenous plaque matrix may be involved in the pro-thrombotic effects. Thus, MPA exhibits differential effects on arterial thrombosis and on atherosclerosis.
authors.affiliation: Institut für Pharmakologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Freudenberger
authors.forename: Marc
authors.initials: M
authors.lastname: Oppermann
authors.forename: Andrea
authors.initials: A
authors.lastname: Marzoll
authors.forename: Hans-Karl
authors.initials: HK
authors.lastname: Heim
authors.forename: Peter
authors.initials: P
authors.lastname: Mayer
authors.forename: Georg
authors.initials: G
authors.lastname: Kojda
authors.forename: Artur A
authors.initials: AA
authors.lastname: Weber
authors.forename: Karsten
authors.initials: K
authors.lastname: Schrör
authors.forename: Jens W
authors.initials: JW
authors.lastname: Fischer
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000633:toxicity; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000494:pharmacology / Q000633:toxicity*; D004967:Estrogens / Q000494:pharmacology / Q000633:toxicity; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010052:Ovariectomy; D015539:Platelet Activation / Q000187:drug effects; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000209:etiology* / Q000503:physiopathology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D001057:Apolipoproteins E; D004967:Estrogens; D004958:Estradiol; D017258:Medroxyprogesterone Acetate; D013917:Thrombin