Effects of estradiol and raloxifene on arterial thrombosis in ovariectomized mice.
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.
Abu-Fanne
Rami
R
Cardiovascular Research Center, Hadassah Hebrew University Medical Center, Kiryat Hadassah, Jerusalem, Israel.
Brzezinski
Amnon
A
Golomb
Mordechai
M
Grad
Etty
E
Foldes
A Joseph
AJ
Shufaro
Yoel
Y
Varon
David
D
Brill
Alexander
A
Lotan
Chaim
C
Danenberg
Haim D
HD
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
D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III