title: Effects of estradiol and raloxifene on arterial thrombosis in ovariectomized mice.
abstract: OBJECTIVE
  The effects of estrogen and selective estrogen receptor modulators (eg, raloxifene) on arterial thrombosis are not well defined. This study assessed the manner and mechanism by which estrogen and raloxifene affect homeostatic pathways in ovariectomized mice after acute arterial injury.
  
  
  METHODS
  Female mice (3 weeks old) underwent ovariectomy or sham operation. Five days after surgery, mice were assigned to treatment with estradiol (5.3 nmol/kg), raloxifene (2.7 micromol/kg), or placebo (n = 10-12/group). The biological effects of both treatments were assessed by measurements of bone mass and the degree of uterine atrophy. After 4 months of therapy, carotid artery thrombosis was induced by photochemical injury, and the time to vascular occlusion was measured.
  
  
  RESULTS
  Both treatments increased bone mineral density (4.1%-7.85%). Reversal of macroscopic uterine atrophy was observed only in estrogen-treated mice. Ovariectomized mice had a shorter time to occlusion compared with sham-operated mice (70.8 +/- 7.4 vs 103 +/- 11.3 min), suggesting accelerated thrombosis. Both estradiol and raloxifene significantly inhibited intra-arterial thrombosis in ovariectomized mice, prolonging the time to occlusion to 136.33 +/- 13.5 and 141.43 +/- 9.26 min, respectively. Cyclooxygenase-2 levels in the lung tissue were significantly increased by both raloxifene and estradiol with endothelial nitric oxide synthase expression being unaltered. Platelet adhesion (measured by surface coverage under a shear rate of 1,800 s for 2 min) was significantly reduced in ovariectomized animals, being 4.63% +/- 1.47%, 5.78% +/- 1.58%, and 10.04% +/- 1.33% for raloxifene, estradiol, and placebo, respectively.
  
  
  CONCLUSIONS
  Ovariectomy amplifies thrombosis. We found that 4 months of treatment with both estradiol and raloxifene attenuates intravascular thrombosis. The antithrombotic effect was accompanied by increased expression of cyclooxygenase-2 and suppression of platelet surface adhesion.
authors.affiliation: Cardiovascular Research Center, Hadassah Hebrew University Medical Center, Kiryat Hadassah, Jerusalem, Israel.
authors.forename: Rami
authors.initials: R
authors.lastname: Abu-Fanne
authors.forename: Amnon
authors.initials: A
authors.lastname: Brzezinski
authors.forename: Mordechai
authors.initials: M
authors.lastname: Golomb
authors.forename: Etty
authors.initials: E
authors.lastname: Grad
authors.forename: A Joseph
authors.initials: AJ
authors.lastname: Foldes
authors.forename: Yoel
authors.initials: Y
authors.lastname: Shufaro
authors.forename: David
authors.initials: D
authors.lastname: Varon
authors.forename: Alexander
authors.initials: A
authors.lastname: Brill
authors.forename: Chaim
authors.initials: C
authors.lastname: Lotan
authors.forename: Haim D
authors.initials: HD
authors.lastname: Danenberg
mesh_terms: D000818:Animals; D001158:Arteries / Q000378:metabolism*; D015519:Bone Density / Q000187:drug effects; D004958:Estradiol / Q000008:administration & dosage*; D005260:Female; D006706:Homeostasis / Q000187:drug effects; D008593:Menopause / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010052:Ovariectomy; D010973:Platelet Adhesiveness / Q000187:drug effects; D020849:Raloxifene Hydrochloride / Q000008:administration & dosage*; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage*; D013927:Thrombosis / Q000378:metabolism* / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III