Das S K, Yano S, Wang J, Edwards D R, Nagase H, Dey S K
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City 66160, USA.
Dev Genet. 1997;21(1):44-54. doi: 10.1002/(SICI)1520-6408(1997)21:1<44::AID-DVG5>3.0.CO;2-8.
The attachment of the blastocyst to the uterine luminal epithelium and the subsequent invasion by trophoblast cells through the stroma and deciduum occur in a highly regulated manner by remodeling of the extracellular matrix. We investigated the temporal and spatial expression of mRNAs for four matrix metalloproteinases (MMPs; MMP-2 [gelatinase A], MMP-3 [stromelysin 1], MMPs; MMP-2 [gelatinase B], and MMP-13 [collagenase 3]) and tissue inhibitors of metalloproteinases (TIMPs; TIMP-1, TIMP-2, and TIMP-3) in the mouse uterus from days 1 to 8 of pregnancy. Northern blot analyses showed the transcripts for MMP-2, MMP-3, RNA on these days. However, MMP-13 mRNA was not detected in the uterus, and only weak signals for MMP-3 mRNA were detected in the myometrium. Striking expression was observed with MMP-2 mRNA in the subepithelial stroma on days 3-5. With the progression of decidualization on day 6, signals were primarily in the secondary decidual zone. On day 8, MMP-2 mRNA was localized at the site of placenta formation in the mesometrial pole. Signals for MMP-9 mRNA were first detected in a small population of stromal cells exclusively at the site of implantation on day 5 at the antimesometrial pole. However, the most pronounced expressed was noted in trophoblast giant cells on day 8. TIMP-1 mRNA was present in the myometrium on day 1. On days 2-5, modest signals were detected in the stroma, and on days 6 and 8, they were in the secondary decidual zone. Localization of TIMP-2 mRNA was similar to that of TIMP-1 except it was restricted to the stroma on day 1. The regulation of TIMP-3 was more pronounced. While a gradual increase in signals was observed in stromal cells from days 1 to 4, strong signals were detected in antimesometrial stromal cells at the sites of blastocyst attachment on day 5. On days 6 and 7, even stronger signals were present in the primary decidual zone surrounding the embryo, and on day 8 signals were localized primarily in the mesometrial decidual bed. These results suggest that MMP-2 may participate in the early phase of decidualization and neovascularization required for placentation. The restricted MMP-9 expression in stromal cells on day 5 and in trophoblast giant cells on day 8, coupled with the expression of TIMP-3 in the stroma surrounding the embryo, suggests that a fine balance between MMP-9 and TIMP-3 may regulate trophoblast invasion in the uterus.
囊胚附着于子宫腔上皮，随后滋养层细胞通过基质和蜕膜进行侵袭，这一过程通过细胞外基质重塑以高度调控的方式发生。我们研究了妊娠第1天至第8天小鼠子宫中四种基质金属蛋白酶（MMPs；MMP - 2[明胶酶A]、MMP - 3[基质溶解素1]、MMP - 9[明胶酶B]和MMP - 13[胶原酶3]）以及金属蛋白酶组织抑制剂（TIMPs；TIMP - 1、TIMP - 2和TIMP - 3）mRNA的时空表达。Northern印迹分析显示了这些天MMP - 2、MMP - 3、MMP - 9的转录本。然而，子宫中未检测到MMP - 13 mRNA，仅在肌层中检测到MMP - 3 mRNA的微弱信号。在第3 - 5天，MMP - 2 mRNA在下上皮基质中观察到显著表达。随着第6天蜕膜化的进展，信号主要位于次级蜕膜区。在第8天，MMP - 2 mRNA定位于子宫系膜极胎盘形成部位。MMP - 9 mRNA信号首先在第5天反子宫系膜极仅植入部位的一小部分基质细胞中检测到。然而，最明显的表达在第8天的滋养层巨细胞中。TIMP - 1 mRNA在第1天存在于肌层中。在第2 - 5天，基质中检测到适度信号，在第6天和第8天，信号位于次级蜕膜区。TIMP - 2 mRNA的定位与TIMP - 1相似，只是在第1天仅限于基质。TIMP - 3的调控更为显著。虽然从第1天到第4天在基质细胞中观察到信号逐渐增加，但在第5天囊胚附着部位的反子宫系膜基质细胞中检测到强信号。在第6天和第7天，围绕胚胎的初级蜕膜区存在更强的信号，在第8天信号主要定位于子宫系膜蜕膜床。这些结果表明，MMP - 2可能参与蜕膜化和胎盘形成所需的早期血管生成阶段。第5天基质细胞和第8天滋养层巨细胞中MMP - 9表达受限，以及胚胎周围基质中TIMP - 3的表达，表明MMP - 9和TIMP - 3之间的精细平衡可能调节滋养层在子宫中的侵袭。
