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Effects of estradiol and raloxifene on arterial thrombosis in ovariectomized mice

Abu-Fanne, Rami MD1; Brzezinski, Amnon MD2; Golomb, Mordechai BSc1; Grad, Etty MSc1; Foldes, A. Joseph MD3; Shufaro, Yoel MD2; Varon, David MD4; Brill, Alexander PhD4; Lotan, Chaim MD1; Danenberg, Haim D. MD1

doi: 10.1097/gme.0b013e318054e2ab
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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.

Design: 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 μmol/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−1 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.

Treatment with estradiol and raloxifene attenuates intravascular thrombosis in ovariectomized mice.

From the 1Cardiovascular Research Center, 2Department of Obstetrics and Gynecology, 3The Jerusalem Osteoporosis Center, and 4Blood Coagulation Unit, Hematology Department, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

Received December 9, 2006; revised and accepted February 28, 2007.

Financial disclosure: None reported.

Address correspondence to: Haim D. Danenberg, MD, Cardiovascular Research Center, Hadassah Hebrew University Medical Center, Kiryat Hadassah, P.O.B. 12000, Jerusalem 91120, Israel. E-mail: danen@md.huji.ac.il

©2008The North American Menopause Society