Zhang X, Wang H M, Lin H Y, Liu G Y, Li Q L, Zhu C
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 25, Bei Si Huan Xi Lu, Haidian District, Beijing 100080, China.
Placenta. 2004 Apr;25(4):243-52. doi: 10.1016/j.placenta.2003.08.014.
Nitric oxide (NO) is believed to play pivotal roles in embryo implantation. The purpose of this study was to investigate the effect of NO on matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), as well as the mechanism of NO during mouse implantation. Nitric oxide synthase (NOS) inhibitor, L-NAME was administered with or without sodium nitroprusside (SNP), NO donor, into one uterine horn on day 3 of pregnancy, and the contralateral uterine horn served as the control. We collected the uteri on days 5, 6, and 7 of pregnancy and examined the mRNA expression of MMP-2, -9, and TIMP-1, -2, -3, as well as the activities of MMP-2 and -9 by using in situ hybridization and gelatin zymography, respectively. The results showed that, compared with the control, the expression of MMP-2 and -9 mRNAs was decreased in L-NAME-treated uteri during peri-implantation. Treatment of mice with L-NAME had slight effect on the expression of TIMP-1 mRNA on day 5 of pregnancy, and no effect on TIMP-2 mRNA expression during peri-implantation. However, the expression of TIMP-3 mRNA was increased. The gelatin zymography results indicated that the activity of MMP-9 was decreased during peri-implantation, but the activity of MMP-2 did not change significantly in these time points examined. The L-NAME-mediated effect on MMPs and TIMPs were significantly reversed when SNP was co-administered with L-NAME. These data suggest that inhibition of NO production regulates the gene expression of MMP-2, -9, and TIMP-3, together with the activity of MMP-9 during peri-implantation, which may have serious consequence on embryo implantation.
一氧化氮（NO）被认为在胚胎着床过程中起关键作用。本研究旨在探讨NO对基质金属蛋白酶（MMPs）及其组织抑制剂（TIMPs）的影响，以及NO在小鼠着床过程中的作用机制。在妊娠第3天，将一氧化氮合酶（NOS）抑制剂L-NAME单独或与NO供体硝普钠（SNP）一起注入一侧子宫角，对侧子宫角作为对照。在妊娠第5、6和7天收集子宫，分别采用原位杂交和明胶酶谱法检测MMP-2、-9以及TIMP-1、-2、-3的mRNA表达，以及MMP-2和-9的活性。结果显示，与对照组相比，在围着床期L-NAME处理的子宫中MMP-2和-9 mRNA的表达降低。L-NAME处理小鼠对妊娠第5天TIMP-1 mRNA的表达有轻微影响，对围着床期TIMP-2 mRNA的表达无影响。然而，TIMP-3 mRNA的表达增加。明胶酶谱结果表明，围着床期MMP-9的活性降低，但在这些检测时间点MMP-2的活性没有显著变化。当SNP与L-NAME共同给药时，L-NAME对MMPs和TIMPs的介导作用被显著逆转。这些数据表明，抑制NO的产生会调节围着床期MMP-2、-9和TIMP-3的基因表达以及MMP-9的活性，这可能对胚胎着床产生严重影响。
