Increased cholesterol decreases uterine activity: functional effects of cholesterol alteration in pregnant rat myometrium
Increased cholesterol decreases uterine activity: functional effects of cholesterol alteration in pregnant rat myometrium
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DOI：
10.1152/ajpcell.00120.2004
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发表时间：
2005-05-01
影响因子：
5.5
通讯作者：
Wray, S
中科院分区：
文献类型：
--
作者：
Smith, RD;Babiychuk, EB;Wray, S
子宫静止对于成功怀孕至关重要。怀孕期间胆固醇和甘油三酯显着升高。胆固醇富含质膜的微区，称为筏和小凹。脂筏和小凹都与细胞信号级联有关。这项工作的目的是研究控制胆固醇含量是否会改变子宫收缩力。妊娠晚期（19-21天）大鼠被人道安乐死，然后解剖纵向子宫肌层。同时记录力和 Ca2+ 测量值，通过在灌注液中添加 5 mg/ml 胆固醇或 0.25 mg/ml 低密度脂蛋白 (LDL) 来增加胆固醇，或者通过在灌注液中添加 2% 甲基-β-环糊精 (MCD) 或 2 U/ml 胆固醇氧化酶来减少胆固醇。 LDL 和胆固醇均能显着抑制自发子宫力的产生和相关的 Ca2+ 瞬变；与之前的对照收缩相比，收缩的频率、幅度和持续时间均显着减少。当使用 1 nM 催产素刺激子宫肌层时，胆固醇也会降低力和 Ca2+。通过 MCD 提取胆固醇或胆固醇氧化酶治疗，子宫活动显着增加。电子显微镜证实了 MCD 的脂筏破坏作用，因为以前的电子显微镜观察显示，在 MCD 治疗后，子宫肌细胞膜上可见的小凹几乎全部消失。这些数据表明子宫平滑肌细胞胆固醇含量对于功能活动至关重要。我们研究的一个新发现是胆固醇会抑制力的产生。它可能是在整个妊娠期间维持子宫静止的机制之一，也可能导致肥胖妇女分娩困难。
Uterine quiescence is essential for successful pregnancy. Cholesterol and triglycerides are markedly increased in pregnancy. Cholesterol is enriched in microdomains of the plasma membrane known as rafts and caveolae. Both lipid rafts and caveolae have been implicated in cellular signaling cascades. The purpose of this work was to investigate whether manipulation of cholesterol content alters uterine contractility. Late pregnancy (19-21 days) rats were humanely euthanized and strips of longitudinal myometrium were then dissected. Force and Ca2+ measurements were simultaneously recorded and cholesterol increased by the addition of 5 mg/ml cholesterol or 0.25 mg/ml low-density lipoproteins (LDLs) or reduced by 2% methyl-beta-cyclodextrin (MCD) or 2 U/ml cholesterol oxidase addition to the perfusate. Both LDLs and cholesterol profoundly inhibited spontaneous uterine force production and associated Ca2+ transients; frequency, amplitude, and duration of contraction were all significantly reduced compared with preceding control contractions. Force and Ca2+ were also reduced by cholesterol when 1 nM oxytocin was used to stimulate the myometrium. Uterine activity was significantly increased by cholesterol extraction with MCD or cholesterol oxidase treatment. Electron microscopy confirmed the lipid raft disrupting effect of MCD, as formerly electron microscopy- visible caveolae in the myometrial cell membrane all but disappeared after MCD treatment. These data show that uterine smooth muscle cell cholesterol content is critically important for functional activity. A novel finding of our study is that cholesterol is inhibitory for force generation. It may be one of the mechanisms operating to maintain uterine quiescence throughout gestation and may also contribute to difficulties in labor suffered by obese women.