Ulrich Craig C, Parker Lauren L, Lambert Janet A, Baldwin Lexa, Buxton Iain L O, Etezadi-Amoli Neda, Leblanc Normand, Burkin Heather R
Department of Pharmacology, University of Nevada, Reno School of Medicine, 1664 North Virginia St., Reno, NV, 89557, USA.
Department of Obstetrics and Gynecology, University of Nevada, Reno School of Medicine, 1664 North Virginia St., Reno, NV, 89557, USA.
Reprod Sci. 2025 Feb;32(2):444-454. doi: 10.1007/s43032-024-01778-3. Epub 2025 Jan 8.
Matrix metallopeptidase 9 (MMP9) is a secreted zinc-dependent peptidase known for extracellular remodeling. MMP9 is elevated in tissues from women experiencing preterm labor, and previous research has shown that the addition of combined matrix metallopeptidases 2 and 9 (MMP2/9) enhances uterine contractions. We hypothesized that adding MMP9 alone would enhance myometrial contractions and that specific MMP9 inhibition would suppress uterine contractions. In myometrial tissue from women undergoing term Caesarean sections, we observed an increased contractile response as measured by area under the curve over time in tissues treated with MMP9 compared to vehicle-treated controls (p = 0.0003). This effect was primarily due to increased contraction frequency in MMP9-treated tissues compared to controls (p < 0.0001). Specific inhibition of MMP9 with the highly selective MMP9 inhibitor 1 (AG-L-66085) reduced contractile responses in myometrial tissues from pregnant women. We observed a reduction in the oxytocin-induced contractile response as measured by area under the curve over time (p < 0.0001) and contraction amplitude (p < 0.0068) in AG-L-66085-treated tissues compared to vehicle-treated controls. To determine the effects of MMP9 inhibition in the absence of exogenous oxytocin, we tested the effects of AG-L-66085 on spontaneous contractions. The area under the curve (p = 0.0415) and amplitude (p = 0.0354) of spontaneous contractions were reduced in response to 1 μM AG-L-66085, and the inhibitory effects increased as the AG-L-66085 concentration increased. Together, these data support the hypothesis that elevated MMP9 promotes myometrial contractions and labor, while its inhibition promotes relaxation.
基质金属蛋白酶9（MMP9）是一种分泌型锌依赖性蛋白酶，以细胞外重塑作用而闻名。MMP9在早产女性的组织中水平升高，先前的研究表明，联合添加基质金属蛋白酶2和9（MMP2/9）可增强子宫收缩。我们推测，单独添加MMP9会增强子宫肌层收缩，而特异性抑制MMP9会抑制子宫收缩。在接受足月剖宫产的女性的子宫肌层组织中，我们观察到，与用赋形剂处理的对照组相比，用MMP9处理的组织中，随着时间推移，曲线下面积测量的收缩反应增加（p = 0.0003）。这种效应主要是由于与对照组相比，MMP9处理的组织中收缩频率增加（p < 0.0001）。用高选择性MMP9抑制剂1（AG-L-66085）特异性抑制MMP9可降低孕妇子宫肌层组织的收缩反应。我们观察到，与用赋形剂处理的对照组相比，在AG-L-66085处理的组织中，随着时间推移，曲线下面积测量的催产素诱导的收缩反应降低（p < 0.0001），收缩幅度降低（p < 0.0068）。为了确定在没有外源性催产素的情况下MMP9抑制的作用，我们测试了AG-L-66085对自发收缩的影响。响应1μM AG-L-66085，自发收缩的曲线下面积（p = 0.0415）和幅度（p = 0.0354）降低，并且随着AG-L-66085浓度增加，抑制作用增强。总之，这些数据支持以下假设：MMP9水平升高促进子宫肌层收缩和分娩，而抑制MMP9则促进子宫松弛。
