Differential effects of medroxyprogesterone acetate on thrombosis and atherosclerosis in mice.
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.
Freudenberger
Till
T
Institut für Pharmakologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
Oppermann
Marc
M
Marzoll
Andrea
A
Heim
Hans-Karl
HK
Mayer
Peter
P
Kojda
Georg
G
Weber
Artur A
AA
Schrör
Karsten
K
Fischer
Jens W
JW
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
D018931:Antineoplastic Agents, Hormonal; D001057:Apolipoproteins E; D004967:Estrogens; D004958:Estradiol; D017258:Medroxyprogesterone Acetate; D013917:Thrombin