雌二醇和雷洛昔芬对去卵巢小鼠动脉血栓形成的影响。

Effects of estradiol and raloxifene on arterial thrombosis in ovariectomized mice.

作者信息

Abu-Fanne Rami, Brzezinski Amnon, Golomb Mordechai, Grad Etty, Foldes A Joseph, Shufaro Yoel, Varon David, Brill Alexander, Lotan Chaim, Danenberg Haim D

机构信息

Cardiovascular Research Center, Hadassah Hebrew University Medical Center, Kiryat Hadassah, Jerusalem, Israel.

出版信息

Menopause. 2008 Jan-Feb;15(1):98-104. doi: 10.1097/gme.0b013e318054e2ab.

DOI:10.1097/gme.0b013e318054e2ab

PMID:17549036

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.

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 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.

摘要

目的

雌激素和选择性雌激素受体调节剂（如雷洛昔芬）对动脉血栓形成的影响尚不明确。本研究评估了雌激素和雷洛昔芬在急性动脉损伤后对去卵巢小鼠体内稳态途径的影响方式及机制。

设计

对3周龄雌性小鼠进行卵巢切除术或假手术。术后5天，将小鼠分为三组，分别用雌二醇（5.3 nmol/kg）、雷洛昔芬（2.7 μmol/kg）或安慰剂治疗（每组n = 10 - 12只）。通过测量骨量和子宫萎缩程度评估两种治疗的生物学效应。治疗4个月后，通过光化学损伤诱导颈动脉血栓形成，并测量血管闭塞时间。

结果

两种治疗均增加了骨矿物质密度（4.1% - 7.85%）。仅在接受雌激素治疗的小鼠中观察到宏观子宫萎缩的逆转。与假手术小鼠相比，去卵巢小鼠的闭塞时间更短（70.8 ± 7.4分钟对103 ± 11.3分钟），表明血栓形成加速。雌二醇和雷洛昔芬均显著抑制去卵巢小鼠的动脉内血栓形成，使闭塞时间分别延长至136.33 ± 13.5分钟和141.43 ± 9.26分钟。雷洛昔芬和雌二醇均使肺组织中环氧化酶 - 2水平显著升高，而内皮型一氧化氮合酶表达未改变。去卵巢动物的血小板黏附（在1800 s的剪切速率下测量2分钟的表面覆盖率）显著降低，雷洛昔芬、雌二醇和安慰剂组分别为4.63% ± 1.47%、5.78% ± 1.58%和10.04% ± 1.33%。