Vascular Surgery Research Laboratory, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, Boston, MA, USA.
Am J Physiol Endocrinol Metab. 2012 Jul 1;303(1):E55-70. doi: 10.1152/ajpendo.00553.2011. Epub 2012 Apr 10.
Normal pregnancy is associated with uterine relaxation to accommodate the stretch imposed by the growing fetus; however, the mechanisms underlying the relationship between pregnancy-associated uterine stretch and uterine relaxation are unclear. We hypothesized that increased uterine stretch during pregnancy is associated with upregulation of matrix metalloproteinases (MMPs), which in turn cause inhibition of myometrium contraction and promote uterine relaxation. Uteri from virgin, midpregnant (day 12), and late-pregnant rats (day 19) were isolated, and myometrium strips were prepared for measurement of isometric contraction and MMP expression and activity using RT-PCR, Western blot analysis, and gelatin zymography. Oxytocin caused concentration-dependent contraction of myometrium strips that was reduced in mid- and late-pregnant rats compared with virgin rats. Pretreatment with the MMP inhibitors SB-3CT (MMP-2/MMP-9 Inhibitor IV), BB-94 (batimastat), or Ro-28-2653 (cipemastat) enhanced contraction in myometrium of pregnant rats. RT-PCR, Western blot analysis, and gelatin zymography demonstrated increased mRNA expression, protein amount, and activity of MMP-2 and MMP-9 in myometrium of late-pregnant>midpregnant>virgin rats. Prolonged stretch of myometrium strips of virgin rats under 8 g basal tension for 18 h was associated with reduced contraction and enhanced expression and activity of MMP-2 and MMP-9, which were reversed by MMP inhibitors. Concomitant treatment of stretched myometrium of virgin rats with 17β-estradiol (E2), progesterone (P4), or E2+P4 was associated with further reduction in contraction and increased MMP expression and activity. MMP-2 and MMP-9 caused significant reduction of oxytocin-induced contraction of myometrium of virgin rat. Thus, normal pregnancy is associated with reduced myometrium contraction and increased MMPs expression and activity. The results are consistent with the possibility that myometrium stretch and concomitant increase in sex hormones during pregnancy are associated with increased expression/activity of specific MMPs, which in turn inhibit uterine contraction and promote uterine relaxation.
正常妊娠伴随着子宫松弛以适应胎儿生长带来的拉伸；然而，妊娠相关子宫拉伸与子宫松弛之间的关系的机制尚不清楚。我们假设，妊娠期间子宫拉伸的增加与基质金属蛋白酶 (MMPs) 的上调有关，而 MMPs 反过来又抑制了子宫肌层收缩并促进了子宫松弛。分离处女、中期妊娠（第 12 天）和晚期妊娠（第 19 天）大鼠的子宫，并使用 RT-PCR、Western blot 分析和明胶酶谱法测量等长收缩和 MMP 表达和活性，准备子宫肌条。催产素引起子宫肌条浓度依赖性收缩，而中期和晚期妊娠大鼠与处女大鼠相比收缩减少。用 MMP 抑制剂 SB-3CT（MMP-2/MMP-9 抑制剂 IV）、BB-94（batimastat）或 Ro-28-2653（cipemastat）预处理增强了妊娠大鼠子宫肌条的收缩。RT-PCR、Western blot 分析和明胶酶谱法显示，晚期妊娠>中期妊娠>处女大鼠的子宫肌层中 MMP-2 和 MMP-9 的 mRNA 表达、蛋白量和活性增加。在 8g 基础张力下将处女大鼠的子宫肌条延长 18 小时与收缩减少以及 MMP-2 和 MMP-9 的表达和活性增强有关，而 MMP 抑制剂则逆转了这一现象。同时用 17β-雌二醇 (E2)、孕酮 (P4) 或 E2+P4 处理处女大鼠伸展的子宫肌层与收缩进一步减少以及 MMP 表达和活性增加有关。MMP-2 和 MMP-9 导致处女大鼠子宫肌层催产素诱导的收缩显著减少。因此，正常妊娠与子宫肌层收缩减少和 MMPs 表达和活性增加有关。结果与以下可能性一致，即妊娠期间子宫拉伸和伴随的性激素增加与特定 MMPs 的表达/活性增加有关，而 MMPs 又抑制子宫收缩并促进子宫松弛。
